tbuckley/cabot-search huggingface dataset:
Biomarker Discovery in Non–Small Cell Lung Cancer: Integrating Gene Expression Profiling, Meta-analysis, and Tissue Microarray Validation
Authors: Johan Botling, Karolina Edlund, Miriam Lohr, Birte Hellwig, Lars Holmberg, Mats Lambe, Anders Berglund, Simon Ekman, Michael Bergqvist, Fredrik Pontén, André König, Oswaldo Fernandes, Mats Karlsson, Gisela Helenius, Christina Karlsson, Jörg Rahnenführer, Jan G Hengstler, Patrick Micke
Journal: Clinical Cancer Research (2012)

Global gene expression profiling has been widely used in lung cancer research to identify clinically relevant molecular subtypes as well as to predict prognosis and therapy response. So far, the value of these multigene signatures in clinical practice is unclear, and the biologic importance of individual genes is difficult to assess, as the published signatures virtually do not overlap.Here, we describe a novel single institute cohort, including 196 non-small lung cancers (NSCLC) with clinical information and long-term follow-up. Gene expression array data were used as a training set to screen for single genes with prognostic impact. The top 450 probe sets identified using a univariate Cox regression model (significance level P < 0.01) were tested in a meta-analysis including five publicly available independent lung cancer cohorts (n = 860).The meta-analysis revealed 14 genes that were significantly associated with survival (P < 0.001) with a false discovery rate <1%. The prognostic impact of one of these genes, the cell adhesion molecule 1 (CADM1), was confirmed by use of immunohistochemistry on tissue microarrays from 2 independent NSCLC cohorts, altogether including 617 NSCLC samples. Low CADM1 protein expression was significantly associated with shorter survival, with particular influence in the adenocarcinoma patient subgroup.Using a novel NSCLC cohort together with a meta-analysis validation approach, we have identified a set of single genes with independent prognostic impact. One of these genes, CADM1, was further established as an immunohistochemical marker with a potential application in clinical diagnostics.
Concurrent and Sequential Administration of Chemotherapy and the Mammalian Target of Rapamycin Inhibitor Temsirolimus in Human Cancer Cells and Xenografts
Authors: Andrea S. Fung, Licun Wu, Ian F. Tannock
Journal: Clinical Cancer Research (2009)

Optimal scheduling of cycle-active chemotherapy with (initially cytostatic) molecular-targeted agents is important to maximize clinical benefit. Concurrent scheduling might allow up-regulation of cell death pathways at the time of chemotherapy, whereas sequential treatments might maximize inhibition of repopulation and avoid putting tumor cells out of cycle when administering cycle-active chemotherapy. We compared the effects of concurrent and sequential administration of chemotherapy and the mammalian target of rapamycin (mTOR) inhibitor temsirolimus (CCI-779) on tumor cells and xenografts.Human prostate cancer PC-3 and LnCaP, and human breast cancer MDA-468 cells and xenografts were treated with chemotherapy (docetaxel and 5-fluorouracil, respectively) and temsirolimus, using concurrent and sequential treatment schedules. Cell killing and repopulation were evaluated by clonogenic assays. Cell cycle analysis was done using flow cytometry. Effects on xenografts were assessed by tumor growth delay.The proliferation of all cell lines was inhibited by temsirolimus in a dose-dependent manner; PTEN negative PC-3 and mutant LnCaP cells were more sensitive than PTEN-negative MDA-468 cells. Temsirolimus inhibited cell cycle progression from G(1) to S phase in all cell lines. Combined treatment had greater effects than temsirolimus or chemotherapy alone: for PC-3 and LnCaP xenografts, concurrent treatment seemed superior to sequential scheduling, whereas MDA-468 cells and xenograft tumors did not show schedule dependence.Combined treatment with temsirolimus and chemotherapy had a greater therapeutic effect than monotherapy; concurrent scheduling was more effective for PC-3 and LnCaP cells and xenografts that were sensitive to temsirolimus.
An Akt/Hypoxia-Inducible Factor-1α/Platelet-Derived Growth Factor-BB Autocrine Loop Mediates Hypoxia-Induced Chemoresistance in Liver Cancer Cells and Tumorigenic Hepatic Progenitor Cells
Authors: Chi Keung Lau, Zhen Fan Yang, David W. Ho, Michael N. Ng, George C.T. Yeoh, Ronnie T.P. Poon, Sheung Tat Fan
Journal: Clinical Cancer Research (2009)

Abstract Purpose: The goals of the present study were to investigate the mechanism of hypoxia-mediated chemoresistance in liver cancer cells and tumorigenic hepatic progenitor (oval) cells and to determine whether disrupting an Akt/hypoxia-inducible factor-1α (HIF-1α)/platelet-derived growth factor (PDGF)-BB autocrine loop can enhance chemotherapeutic efficacy in hypoxia. Experimental Design: Five hepatocellular carcinoma (HCC) cell lines and two hepatic progenitor cell lines were treated in vitro with cisplatin under both normoxic and hypoxic conditions. To generate ischemic hypoxia for tumor cells in vivo, hepatic artery ligation was applied to an orthotopic HCC model. Cisplatin and YC1, which is a HIF-1α inhibitor, were administered by portal vein and intratumoral injections, respectively. Results: Cell viability was higher under hypoxic than normoxic conditions. HIF-1α and Akt were up-regulated under hypoxic conditions, forming an autocrine signaling loop with PDGF-BB. Akt/HIF-1α/PDGF-BB signaling regulated Akt to confer cisplatin resistance to HCC cell lines in vitro. This autocrine signaling loop also contributed to chemoresistance in the tumorigenic hepatic progenitor cell line PIL2 under hypoxic conditions but not in the nontumorigenic cell line PIL4. In an orthotopic HCC model, combining blockade of HIF-1α activity with ischemic hypoxia significantly enhanced the efficacy of chemotherapy, leading to suppression of tumor growth and prolongation of animal survival. Conclusion: Blockade of Akt/HIF-1α/PDGF-BB autocrine signaling could enhance the chemosensitivity of liver cancer cells and tumorigenic hepatic progenitor cells under hypoxic conditions and thus provide an effective therapeutic strategy for HCC.
C-Reactive Protein and Glycemic Control in Adults With Diabetes
Authors: Dana E. King, Arch G. Mainous, Thomas A. Buchanan, William S. Pearson
Journal: Diabetes Care (2003)

OBJECTIVE—Recent evidence suggests that poor glycemic control is significantly associated with the development of macrovascular complications of diabetes. Studies have indicated that C-reactive protein (CRP) is an important risk factor for cardiovascular disease. The purpose of this study was to determine the relation between CRP and HbA1c in a large national sample of individuals with diabetes. RESEARCH DESIGN AND METHODS—A nationally representative sample of noninstitutionalized U.S. adults aged 17 years and over with nongestational diabetes was derived from the National Health and Nutrition Examination Survey III (1988–1994) (n = 1,018). Respondents with diabetes were stratified by HbA1c level. The main outcome measure was elevated (&amp;gt;0.30 mg/dl) CRP. RESULTS—In unadjusted analyses, respondents with diabetes who had elevated HbA1c levels (≥9.0%) had a significantly higher percent of elevated CRP than people with low (&amp;lt;7%) HbA1c levels (P &amp;lt; 0.001). In adjusted regression analysis, after controlling for age, race, sex, smoking, length of time with diabetes, insulin, and BMI, HbA1c was significantly associated with an increased likelihood of elevated CRP for HbA1c &amp;gt;9.0% (OR 2.15, 95% CI 1.07–4.32) and for HbA1c &amp;gt;11.0% (4.40, 1.87–10.38). Higher HbA1c also predicted elevated CRP in the regression model when HbA1c was analyzed as a continuous variable (1.20, 1.07–1.34). CONCLUSIONS—In this study, the likelihood of elevated CRP concentrations increased with increasing HbA1c levels. These findings suggest an association between glycemic control and systemic inflammation in people with established diabetes.
Elevated plasma osteopontin associated with gastric cancer development, invasion and survival
Authors: C.-Y. Wu, M.-S. Wu, E.-P. Chiang, C.-C. Wu, Y.-J. Chen, C.-J. Chen, N.-H. Chi, G.-H. Chen, J.-T. Lin
Journal: Gut (2006)

Osteopontin (OPN) has been found to be valuable in diagnosis and predicting the prognosis of a variety of malignancies. The aims of the present study are to evaluate the usefulness of plasma OPN level for predicting gastric cancer development, invasion and survival.One hundred and thirty two gastric cancer patients and 93 healthy controls were enrolled. Real-time quantitative reverse-transcription polymerase chain reaction and immunohistochemical staining were used to detect OPN expression in gastric cancer tissues. Plasma levels of OPN were measured by enzyme-linked immunosorbent assay. Plasma OPN levels were compared with gastric cancer development, clinicopathological features and outcomes.Expression of OPN mRNA was significantly higher in gastric cancer tissues compared with non-tumour tissues. Most OPN immunoactivity was localised to cancer cells. The median plasma OPN level was significantly higher in patients than in controls (p<0.0001), and significantly higher in patients with advanced stages, serosal invasion, lymph node metastasis, lymphatic invasion, venous invasion and liver metastasis. Logistic regression showed that high plasma OPN level (greater than 67.3 ng/ml) is significantly associated with advanced stages, serosal invasion, lymph node metastasis, lymphatic invasion, venous invasion and liver metastasis. Plasma OPN level demonstrated significant association with patient survival (p<0.0001), especially in the subgroups with invasive phenotypes. On Cox multivariate analysis, elevated plasma OPN level was an independent risk factor for poor survival (p<0.0001).Elevated plasma OPN level is significantly associated with gastric cancer development, invasive phenotypes and survival. Plasma OPN level may have potential usefulness as a diagnostic and prognostic factor for gastric cancer.
Activation of Ca2+-independent nitric oxide synthase by 17β-estradiol in post-ischemic rat heart
Authors: H Fraser
Journal: Cardiovascular Research (2000)

Background: Nitric oxide (NO) donors or facilitation of endogenous NO production is cardioprotective. This study sought to determine whether enhanced myocardial NO production might contribute to estrogen-induced cardioprotection. Methods: Ca2+-dependent and Ca2+-independent NOS activities (pmol min−1 mg−1 protein), NOS protein expression (quantitative immunoblot), cGMP content (pmol mg−1 protein) and LV work (Joules) were measured in hearts isolated from ovariectomized rats that were either untreated or treated chronically with 17β-estradiol (0.25 mg, 21 day release formulation). Results: After 14 days, serum levels of 17β-estradiol were 6±1 and 135±16 pg ml−1 in untreated and 17β-estradiol-treated animals, respectively. After 60 min aerobic working mode perfusion, Ca2+-dependent NOS (untreated, 1.47±0 36; 17β-estradiol 1.13±0.25) and Ca2+-independent NOS (untreated, 0.45±0.24; 17β-estradiol, 0.41±0.21) activities, eNOS and iNOS proteins and cGMP content (untreated, 0.64±0.08; 17β-estradiol, 0.76±0.12) were not different in the two groups. After 60 min low-flow (0.5 ml min−1) ischemia and 30 min reperfusion, Ca2+-dependent NOS activities were again similar (untreated, 1.25±0.23; 17β-estradiol, 0.78±0.27). However, after reperfusion, Ca2+-independent NOS activity (untreated, 0.39±0.10; 17β-estradiol, 1.36±0.36) was 3.5-fold higher (P=0.008) and cGMP content (untreated, 0.30±0.03; 17β-estradiol, 0.49±0.07) was 1.6-fold higher (P=0.017) in hearts from 17β-estradiol-treated animals. Although pre-ischemic function was similar, recovery of post-ischemic LV work was 2-fold greater (P=0.024) in the 17β-estradiol group. Conclusion: The ability of ischemia and reperfusion in combination with chronic 17β-estradiol to increase Ca2+-independent NOS activity and cGMP content supports a role for enhanced myocardial NO signaling in 17β-estradiol-induced cardioprotection.
The Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) study
Authors: Brian Olshansky, Lynda E. Rosenfeld, Alberta L. Warner, Allen J. Solomon, Gearoid O'Neill, Arjun Sharma, Edward Platia, Gregory K. Feld, Toshio Akiyama, Michael A. Brodsky, H.Leon Greene
Journal: Journal of the American College of Cardiology (2004)
A British Medical Association Lecture on SOME MODERN ASPECTS OF NEPHRITIS
Authors: W. L. Brown
Journal: BMJ (1929)

T'nie centenar celebrationi last y-ear of te pulll)licatioli (f Richard Bright's discovery cauised hiis -ork to be ye-examiiined with greater care.As with Darwin, so witlh l3itglft, a study of thleir owrn w-r itinigs maakes uls realize LOWiiiullch more cautiously they exl)ressed their conclusions tlan their followers have donie.Tlle disciple alw-ays tends to be miiore Royalist than the Kinig.Asclhoff says: Briglht himself, with characteristic cauition, (liscussed the question of tlho extent to which all the symiiptomiis described by him shloutld be referred to pri-mary disease of the kidneys or to primary lesions of other orgains.It is, tllerefore, bettel to speak of symptoms of l3right's (liscase in disorders of the 1,idneys and not of Bright's (lisease of tlhe kidney."He sllitests limiting symptomis to tlhe combination of toxic 1d inflamimatory albumiiuLiria with so-called renial oedemna.Thtis woutld exclude some forms of niepliritis, suclh as granuilar kidney.In general, nophritis is duie to some1 toxic cauise.T dTo ]ot believe that mere exposure ix) ccoild cauises lleplhritis in healthy kidney, though it may exacerbate a chronic lesion which is already presenit.In the great war tllo epidemic of nephritis did not occLir dutrinig the first winter wlheni men were muclh exposed anid badly lhoused; it occulrred during the early sprinig of 1915, an-d thlere was iio relationship between low telmperature and tlhe ineidtence of nieplhritis.It was then suggested that a gireat range of teinperaturo was an exciting caeuse, but in the Boer wvar, whOen I saw the mirage at 2 o'clock in the afternooln and hoar frost at4 6.30 on the veldlt niear Bloemllfontein, cases of acuto nephritis were almost uiniiknown.On the other lhanid, in subsequent wviiters in the g;reat w-ar there -as some agreement between low temiiperature alld tllc onset of acute nephriti8, because by that timc thele wer-c coniside,rable number of men in the field wvhose kidnieyss lhad ]I cviously been somewhat daniiaged.
Severe Atherosclerosis and Hypoalphalipoproteinemia in the Staggerer Mouse, a Mutant of the Nuclear Receptor RORα
Authors: Anna Mamontova, Sandrine Séguret-Macé, Bruno Esposito, Colette Chaniale, Muriel Bouly, Nicole Delhaye-Bouchaud, Gérald Luc, Bart Staels, Nicolas Duverger, Jean Mariani, Alain Tedgui
Journal: Circulation (1998)

Hypoalphalipoproteinemia is the most common lipoprotein abnormality in patients with coronary artery disease, yet its causes are unknown.We show that the homozygous staggerer (sg/sg) mutant mouse, which carries a deletion within the nuclear receptor RORalpha gene, develops severe atherosclerosis when maintained on an atherogenic diet. In addition, sg/sg mice display a profound hypoalphalipoproteinemia, which is associated with decreased plasma levels of the major HDL proteins, apolipoprotein (apo) A-I and apoA-II. This decrease in HDL levels in sg/sg mice is due to lowered apoA-I gene expression in the intestine but not in the liver. ApoA-II gene expression is unaffected.These results suggest that the RORalpha gene contributes to the plasma HDL level and susceptibility to atherosclerosis.
Establishment and immunological characterization of cultured human gallbladder epithelial cells
Authors: Marcus K. H. Auth, Raymond A. Keitzer, Martin Scholz, Roman A. Blaheta, Christoph E. Hottenrott, Günther Herrmann, Albrecht Encke, Bernd H. Markus
Journal: Hepatology (1993)

Biliary epithelial cells are a primary site of damage in liver allograft rejection and in immunologically mediated diseases such as primary biliary cirrhosis. Human leukocyte antigens and adhesion molecules on the biliary epithelium are associated with T-lymphocytic binding, recognition and destruction. To investigate relevant cellular immunological mechanisms under standard conditions, we have established an in vitro model using human gallbladder epithelial cells. Although not directly affected in these aberrations, gallbladder epithelial cells are excellent objects for immunological investigations. More than 10(8) highly purified cells were isolated and cultured longer than 6 wk in confluent monolayers. Cell growth was routinely established on uncoated plastic culture dishes, and serum-free media could be applied for immunological experiments. Cell characterization was performed by means of specific monoclonal antibodies typical for biliary epithelial cells. Cytokeratins 1 through 8, 18 and 19 and human epithelial cell antibody 125 always showed strong positive staining. Antigen patterns were examined before and after treatment with interferon-gamma by use of immunohistochemical staining methods. Untreated human gallbladder epithelial cells expressed human leukocyte class I antigens but few or no class II antigens. After stimulation with interferon-gamma induction of human leukocyte antigen-DR, -DP and -DQ was detected. In addition, intercellular adhesion molecule 1 was induced on these gallbladder epithelial cells. Therefore an immunological competence similar to that of biliary epithelial cells could be demonstrated. In vitro cell cultures of gallbladder epithelial cells offer a promising tool for subsequent investigations concerning intrahepatic biliary epithelial cells and their interactions with cells of the immune system.
Stimulation of TLR2 and TLR4 differentially skews the balance of T cells in a mouse model of arthritis
Authors: Shahla Abdollahi-Roodsaz, Leo A.B. Joosten, Marije I. Koenders, Isabel Devesa, Mieke F. Roelofs, Timothy R.D.J. Radstake, Marleen Heuvelmans-Jacobs, Shizuo Akira, Martin J.H. Nicklin, Fátima Ribeiro-Dias, Wim B. van den Berg
Journal: Journal of Clinical Investigation (2008)

TLRs may contribute to the progression of rheumatoid arthritis through recognition of microbial or host-derived ligands found in arthritic joints. Here, we show that TLR2 and TLR4, but not TLR9, are involved in the pathogenesis of autoimmune arthritis and play distinct roles in the regulation of T cells and cytokines. We investigated the involvement of TLR2, TLR4, and TLR9 in the progression of arthritis using IL-1 receptor antagonist–knockout (IL1rn–/–) mice, which spontaneously develop an autoimmune T cell–mediated arthritis. Spontaneous onset of arthritis was dependent on TLR activation by microbial flora, as germ-free mice did not develop arthritis. Clinical and histopathological evaluation of IL1rn–/–Tlr2–/– mice revealed more severe arthritis, characterized by reduced suppressive function of Tregs and substantially increased IFN-γ production by T cells. IL1rn–/–Tlr4–/– mice were, in contrast, protected against severe arthritis and had markedly lower numbers of Th17 cells and a reduced capacity to produce IL-17. A lack of Tlr9 did not affect the progression of arthritis. While any therapeutic intervention targeting TLR2 still seems complicated, the strict position of TLR4 upstream of a number of pathogenic cytokines including IL-17 provides an interesting potential therapeutic target for rheumatoid arthritis.
Vasodilation to Bradykinin Is Mediated by an Ouabain-Sensitive Pathway as a Compensatory Mechanism for Impaired Nitric Oxide Availability in Essential Hypertensive Patients
Authors: Stefano Taddei, Lorenzo Ghiadoni, Agostino Virdis, Simona Buralli, Antonio Salvetti
Journal: Circulation (1999)

In essential hypertension, endothelium-dependent vasodilation is impaired because of reduced nitric oxide (NO) availability, which is mainly caused by oxidative stress. The present study was designed to identify the mechanism(s) responsible for NO-independent vasodilation to bradykinin in patients with essential hypertension.In 16 healthy subjects (49.5+/-5.8 years; 118.6+/-3.5/78.9+/-2.9 mm Hg) and 16 patients with essential hypertension (47.9+/-4.8 years; 154.6+/-4.5/102.9+/-3.2 mm Hg), we measured modifications in forearm blood flow (strain-gauge plethysmography) during intrabrachial infusion of bradykinin (5, 15, or 50 ng/100 mL of forearm tissue per minute) in the presence of saline, N(omega)-monomethyl-L-arginine (L-NMMA; used to inhibit NO synthase; 100 microg/100 mL of forearm tissue per minute), and ouabain (to block Na(+)K(+)/ATPase and prevent hyperpolarization; 0.7 microg/100 mL of forearm tissue per minute). In healthy subjects, vasodilatation to bradykinin was significantly blunted by L-NMMA and unaffected by ouabain. In hypertensive patients, vasodilatation to bradykinin was not modified by L-NMMA, but it was significantly reduced by ouabain. In an adjunctive group of 8 hypertensive patients (49.9+/-3.8 years; 155.9+/-5.5/103.7+/-3.9 mm Hg), the response to bradykinin was repeated during the administration of intrabrachial vitamin C (a scavenger for oxygen free radicals; 8 mg/100 mL of forearm tissue per minute). In these patients, L-NMMA-induced inhibition of vasodilation to bradykinin was restored, and ouabain was no longer effective. In a final group of 6 normotensive controls (45.9+/-4.1 years; 115.1+/-2.9/79.3+/-2.1 mm Hg), vasodilation to bradykinin residual to L-NMMA blockade was further inhibited by simultaneous ouabain infusion.Vasodilation to bradykinin is impaired in essential hypertensive patients because of an NO-system alteration caused by oxidative stress, and it is mediated by an alternative pathway, possibly involving endothelium-dependent hyperpolarization.
Efficacy of Mandatory Seat-Belt Use Legislation
Authors: Terence L. Chorba
Journal: JAMA (1988)

The North Carolina General Assembly approved a law effective in October 1985 that mandated seat-belt use by front-seat occupants of passenger vehicles. In January 1987, a $25 fine for infractions of this law went into effect. This study examined numbers of car occupants with severe and fatal injuries in crashes in North Carolina, controlling for the amount of vehicle damage as a measure of crash severity. After the law, significant decreasing trends were seen in the percentages of front-seat occupants who had severe or fatal injuries in crashes, although the involvement of alcohol in crashes was still associated with an increased risk of such injury. Projections indicate that a reduction of approximately 1100 severe or fatal injuries per year can be attributed to the seat-belt law in North Carolina. This study supports the hypothesis that the societal burden of crash-associated injury can be reduced by mandating seat-belt use. (<i>JAMA</i>1988;260:3593-3597)
TEM8 specific T cells target the tumor cells and tumor-associated vasculature in triple negative breast cancer
Authors: Tiara Byrd, Kristen Fousek, Antonella Pignata, Amanda Wakefield, Brad St Croix, Bradley S Fletcher, Meenakshi Hegde, Nabil Ahmed
Journal: Journal for ImmunoTherapy of Cancer (2014)

Meeting abstracts Tumor endothelium marker 8 (TEM8) was discovered by St Croix, et. al. as one of nine gene products preferentially upregulated in the tumor-associated vs. normal endothelium [[1][1]]. Interestingly, TEM8 has also been identified as a tumor restricted antigen in triple negative