tbuckley/cabot-search huggingface dataset:
Anti-tumour necrosis factor therapy in Crohn's disease: where are we now?
Authors: S J H van Deventer
Journal: Gut (2002)

Controlled trials have confirmed the efficacy of two tumour necrosis factor α (TNF-α) antibodies in active Crohn’s disease.1–4 In responding patients, the therapeutic effects qualitatively differ from those observed with standard therapy, including corticosteroids and immunosuppressives, and complete clinical remission can be induced in about one third of patients that did not respond to standard treatment. More than 140 000 patients have been treated with infliximab, and in large centres the reported efficacy in Crohn’s disease is comparable with data reported in controlled clinical trials. Few would disagree that anti-TNF-α therapy is an important therapeutic addition in the treatment of patients with active Crohn’s disease. On the other hand, toxicities related to TNF-α neutralising therapies have emerged. Of 147 000 infliximab treated patients, 70 developed tuberculosis, and 12 subsequently died (four as a direct result of tuberculosis).5

The importance of TNF-α for the host defence against Mycobacterium tuberculosis ,6 Listeria monocytogene , and other intracellular pathogens is long known, and it should come as no surprise that neutralisation of TNF-α predisposes to (reactivation of) tuberculosis. Indeed, tuberculosis has been reported in etanercept (a TNF receptor II fusion protein) and D2E7 (a human anti-TNF-α antibody) treated patients. In the majority of cases, tuberculosis following treatment with …
Vascular smooth muscle response to ouabain. Relation of tissue Na+ to the contractile response.
Authors: L Stewart, C Hamilton, J Ingwall, S Naomi, S Graves, M Canessa, G Williams, N Hollenberg
Journal: Circulation Research (1993)

Smooth muscle responses to Na+ pump inhibition are thought to reflect two elements: a neurogenic contribution, involving catecholamine release from nerve terminals, and a myogenic response, attributed to relations between pump activity, [Na+]i, and [Ca2+]i. In the present study, we describe the time course and magnitude of cell Na+ changes, assessed by two methods, atomic absorption and nuclear magnetic resonance spectroscopy during the myogenic contractile response of rabbit aorta strips to ouabain. A threshold concentration of 3 x 10(-7) mol/L induced a gradual rise in [Na+]i. Both methods showed an essentially identical monotonic rise over 4 to 8 hours from a baseline level of 8 to 10 mmol/L water to a peak, which was approximately fivefold higher. The neurogenic (rapid) and myogenic (delayed and gradual) contractile responses were temporally distinct. Ouabain at 10(-7) mol/L, a concentration 10- to 100-fold lower than the threshold for catecholamine-dependent rapid-onset responses, induced only a delayed and gradual contractile response, which reached a maximum at 6 to 8 hours. With 10(-6) mol/L ouabain, the delayed response of 1.6 +/- 0.2 g peaked at 7.3 +/- 1.1 hours and was sustained for 16 hours. The time course was similar to that for change in [Na+] but somewhat later. Ouabain at 10(-5) and 10(-4) mol/L induced a delayed response that was identical in magnitude but also induced an early rapid contractile response, which was prevented by reserpine or phentolamine pretreatment. These agents did not influence the delayed response.(ABSTRACT TRUNCATED AT 250 WORDS)
Vulnerabilities of <i>PTEN</i>–<i>TP53</i>-Deficient Prostate Cancers to Compound PARP–PI3K Inhibition
Authors: Enrique González-Billalabeitia, Nina Seitzer, Su Jung Song, Min Sup Song, Akash Patnaik, Xue-Song Liu, Mirjam T. Epping, Antonella Papa, Robin M. Hobbs, Ming Chen, Andrea Lunardi, Christopher Ng, Kaitlyn A. Webster, Sabina Signoretti, Massimo Loda, John M. Asara, Caterina Nardella, John G. Clohessy, Lewis C. Cantley, Pier Paolo Pandolfi
Journal: Cancer Discovery (2014)

Prostate cancer is the most prevalent cancer in males, and treatment options are limited for advanced forms of the disease. Loss of the PTEN and TP53 tumor suppressor genes is commonly observed in prostate cancer, whereas their compound loss is often observed in advanced prostate cancer. Here, we show that PARP inhibition triggers a p53-dependent cellular senescence in a PTEN-deficient setting in the prostate. Surprisingly, we also find that PARP-induced cellular senescence is morphed into an apoptotic response upon compound loss of PTEN and p53. We further show that superactivation of the prosurvival PI3K-AKT signaling pathway limits the efficacy of a PARP single-agent treatment, and that PARP and PI3K inhibitors effectively synergize to suppress tumorigenesis in human prostate cancer cell lines and in a Pten/Trp53-deficient mouse model of advanced prostate cancer. Our findings, therefore, identify a combinatorial treatment with PARP and PI3K inhibitors as an effective option for PTEN-deficient prostate cancer.The paucity of therapeutic options in advanced prostate cancer displays an urgent need for the preclinical assessment of novel therapeutic strategies. We identified differential therapeutic vulnerabilities that emerge upon the loss of both PTEN and p53, and observed that combined inhibition of PARP and PI3K provides increased efficacy in hormone-insensitive advanced prostate cancer.
Lipopolysaccharide (LPS)-binding protein is carried on lipoproteins and acts as a cofactor in the neutralization of LPS.
Authors: M M Wurfel, S T Kunitake, H Lichenstein, J P Kane, S D Wright
Journal: The Journal of Experimental Medicine (1994)

Lipoproteins isolated from normal human plasma can bind and neutralize bacterial lipopolysaccharide (LPS) and may represent an important mechanism in host defense against gram-negative septic shock. Recent studies have shown that experimentally elevating the levels of circulating high-density lipoproteins (HDL) provides protection against death in animal models of endotoxic shock. We sought to define the components of HDL that are required for neutralization of LPS. To accomplish this we have studied the functional neutralization of LPS by native and reconstituted HDL using a rapid assay that measures the CD14-dependent activation of leukocyte integrins on human neutrophils. We report here that reconstituted HDL particles (R-HDL), prepared from purified apolipoprotein A-I (apoA-I) combined with phospholipid and free cholesterol, are not sufficient to neutralize the biologic activity of LPS. However, addition of recombinant LPS binding protein (LBP), a protein known to transfer LPS to CD14 and enhance responses of cells to LPS, enabled prompt binding and neutralization of LPS by R-HDL. Thus, LBP appears capable of transferring LPS not only to CD14 but also to lipoprotein particles. In contrast with R-HDL, apoA-I containing lipoproteins (LpA-I) isolated from plasma by selected affinity immunosorption (SAIS) on an anti-apoA-I column, neutralized LPS without addition of exogenous LBP. Several lines of evidence demonstrated that LBP is a constituent of LpA-I in plasma. Passage of plasma over an anti-apoA-I column removed more than 99% of the LBP detectable by ELISA, whereas 31% of the LBP was recovered by elution of the column. Similarly, the ability of plasma to enable activation of neutrophils by LPS (LBP/Septin activity) was depleted and recovered by the same process. Furthermore, an immobilized anti-LBP monoclonal antibody coprecipitated apoA-I. The results described here suggest that in addition to its ability to transfer LPS to CD14, LBP may also transfer LPS to lipoproteins. Since LBP appears to be physically associated with lipoproteins in plasma, it is positioned to play an important role in the neutralization of LPS.
Systems biology-defined NF-κB regulons, interacting signal pathways and networks are implicated in the malignant phenotype of head and neck cancer cell lines differing in p53 status
Authors: Bin Yan, Guang Chen, Kunal Saigal, Xinping Yang, Shane T Jensen, Carter Van Waes, Christian J Stoeckert, Zhong Chen
Journal: Genome biology (2008)

Aberrant activation of the nuclear factor kappaB (NF-kappaB) pathway has been previously implicated as a crucial signal promoting tumorigenesis. However, how NF-kappaB acts as a key regulatory node to modulate global gene expression, and contributes to the malignant heterogeneity of head and neck cancer, is not well understood.To address this question, we used a newly developed computational strategy, COGRIM (Clustering Of Gene Regulons using Integrated Modeling), to identify NF-kappaB regulons (a set of genes under regulation of the same transcription factor) for 1,265 genes differentially expressed by head and neck cancer cell lines differing in p53 status. There were 748 NF-kappaB targets predicted and individually annotated for RELA, NFkappaB1 or cREL regulation, and a prevalence of RELA related genes was observed in over-expressed clusters in a tumor subset. Using Ingenuity Pathway Analysis, the NF-kappaB targets were reverse-engineered into annotated signature networks and pathways, revealing relationships broadly altered in cancer lines (activated proinflammatory and down-regulated Wnt/beta-catenin and transforming growth factor-beta pathways), or specifically defective in cancer subsets (growth factors, cytokines, integrins, receptors and intermediate kinases). Representatives of predicted NF-kappaB target genes were experimentally validated through modulation by tumor necrosis factor-alpha or small interfering RNA for RELA or NFkappaB1.NF-kappaB globally regulates diverse gene programs that are organized in signal networks and pathways differing in cancer subsets with distinct p53 status. The concerted alterations in gene expression patterns reflect cross-talk among NF-kappaB and other pathways, which may provide a basis for molecular classifications and targeted therapeutics for heterogeneous subsets of head and neck or other cancers.
Induction of iNOS expression in skeletal muscle by IL-1β and NFκB activation: an in vitro and in vivo study
Authors: V Adams
Journal: Cardiovascular Research (2002)

The intracellular pathway and the regulation of inducible nitric oxide synthase (iNOS) expression in skeletal muscle is incompletely understood. In vitro studies, using different cell types, suggest that inflammatory cytokines are potential triggers to induce iNOS expression.To analyze intracellular pathways leading to iNOS induction, rat skeletal myoblasts were incubated with inflammatory cytokines and assessed for iNOS expression by Western blot and Griess reaction. To confirm the in vitro findings, local cytokine levels were determined in skeletal muscle biopsies of patients with chronic heart failure (CHF) and correlated with iNOS expression.Nitrite accumulation in the myoblast culture supernatant or iNOS protein in the cell pellet was significantly increased after incubation with IL-1beta in combination with gamma-IFN. Priming experiments revealed that gamma-IFN elevated the expression of IL-1beta receptor mRNA, whereby IL-1beta was able to induce iNOS expression. The cytokine-mediated iNOS induction was significantly reduced by blocking ERK1/ERK2 activation and completely abolished by the inhibition of NFkappaB. In skeletal muscle biopsies of CHF patients the local content of IL-1beta was significantly increased as compared to healthy controls. Furthermore, a linear correlation between IL-1beta content and iNOS expression in the skeletal muscle was detected.These data demonstrate that IL-1beta, together with the priming effect of gamma-IFN, induces iNOS expression in skeletal muscle via activation of ERK1/ERK2 and NFkappaB.
Influenza vaccination and mortality: prospective cohort study of the elderly in a large geographical area
Authors: Å. Örtqvist, F. Granath, J. Askling, J. Hedlund
Journal: European Respiratory Journal (2007)

The 50% reduced overall mortality previously associated with influenza vaccination among the elderly was based on studies neither fully taking into account systematic differences between individuals who accept or decline vaccination nor encompassing the entire general population. A population-based prospective cohort study was performed in Stockholm County (Sweden), including all persons aged ≥65 yrs (n = ∼260,000), over three influenza seasons: 1998/1999, 1999/2000 and 2000/2001. The relative risks of mortality among vaccinated versus unvaccinated individuals were estimated using Cox's proportional hazards regression adjusted for, and stratified by, demographic factors and comorbid conditions during the three seasons and the respective following off-seasons. Influenza vaccination was associated with an unadjusted reduction in all-cause mortality during the three seasons of 50, 46 and 42%, respectively, which decreased to 14, 19 and 1%, respectively, following adjustment for confounders and differences in mortality between vaccinated and unvaccinated individuals following the influenza season. The numbers needed to treat to prevent one death, during the three seasons, were 297, 158 and 743, respectively. Vaccination remains the most important measure for prevention of influenza complications in elderly people, although the effectiveness in reducing all-cause mortality in elderly persons is lower than previously thought.
Defining Pain Terms
Authors: Rudolph H. de Jong
Journal: JAMA (1980)

THE MEANING of many terms we use in medicine can be interpreted in various ways, depending on who does the interpreting. Partly that is because some terms defy precise definition, partly because we use terms loosely, and partly because of differences in cultural and educational backgrounds. With the English language assuming the role of lingua franca, the possibility of misinterpretation is further compounded when medical terms are applied by physicians with limited fluency in English. Ethnic shadings and subtle differences in local meaning introduced by direct translation could well obscure the original author's true intent. In an amorphous field such as the care and study of pain—where words are colored by experience, tradition, culture, and surroundings—uniformity of verbal and written communication was thought to be well-nigh impossible. Yet it is vitally important to the patient suffering from pain that each attending physician understand precisely what other colleagues observed and elicited,
Combined Effects of Tobacco Smoke Exposure and Metabolic Syndrome on Cardiovascular Risk in Older Residents of China
Authors: Yao He, Tai Hing Lam, Bin Jiang, Jie Wang, Xiaoyong Sai, Li Fan, Xiaoying Li, Yinhe Qin, Frank B. Hu
Journal: Journal of the American College of Cardiology (2009)
Eradication of Barrett’s mucosa with argon plasma coagulation and acid suppression: immediate and mid term results
Authors: J-L Van Laethem, M Cremer, M O Peny, M Delhaye, J Devière
Journal: Gut (1998)

Background —Intestinal metaplastic mucosa in Barrett’s oesophagus can be replaced by squamous epithelium after mucosal thermal ablation associated with acid suppression therapy. Aims —To assess whether restoration of squamous epithelium can be obtained after ablation of Barrett’s oesophagus using argon plasma coagulation (APC) associated with proton pump inhibitor (PPI) therapy. Methods —Thirty one patients with Barrett’s oesophagus received APC. Omeprazole (40 mg/day) was given from the first APC application to one month after completion of the treatment, then given symptomatically. Twenty four hour pH-metry was performed during endotherapy. Results —Complete re-epithelialisation was visualised at endoscopy in 25/31 patients (81%) after a mean number of 2.4 APC sessions (range 1–4). Only partial squamous re-epithelialisation was observed in three patients and three others had no eradication. At histological assessment, eradication of Barrett’s oesophagus was only confirmed in 19/31 patients (61%) due to the presence of a few residual Barrett’s glands under the new squamous epithelium. Complete eradication was related to a Barrett’s oesophagus segment length of less than 4 cm and the absence of circumferential extension but not to the normalisation of oesophageal acid exposure under PPI therapy. Seventeen patients with apparently complete endoscopic and histological eradication of Barrett’s oesophagus were re-evaluated at one year; eight (47%) disclosed relapsing islands of Barrett metaplasia despite continuous omeprazole therapy (10–40 mg/day). Conclusions —APC combined with 40 mg omeprazole daily can eradicate Barrett’s mucosa with apparent squamous re-epithelialisation in the majority of patients even in the absence of normalisation of oesophageal acid exposure. However, one year after endotherapy for Barrett’s oesophagus, relapse is frequent but limited in extent.
Manufacture and Cytotoxicity of a Lead‐free Piezoelectric Ceramic as a Bone Substitute—Consolidation of Porous Lithium Sodium Potassium Niobate by Cold Isostatic Pressing
Authors: Qi Wang, Jun Yang, Wu Zhang, Roxanne Khoie, Yi‐ming Li, Jian‐guo Zhu, Zhi‐qing Chen
Journal: International Journal of Oral Science (2009)

The piezoelectric properties and cytotoxicity of a porous lead‐free piezoelectric ceramic for use as a direct bone substitute were investigated. Cold isostatic pressing (CIP) was applied to fabricate porous lithium sodium potassium niobate (Li0.06Na0.5K0.44) NbO3 specimens using a pore‐forming method. The morphologies of the CIP‐processed specimens were characterized and compared to those of specimens made by from conventional pressing procedures. The effects of the ceramic on the attachment and proliferation of osteoblasts isolated from the cranium of 1‐day‐old Sprague‐Dawley rats were examined by a scanning electron microscopy (SEM) and methylthiazol tetrazolium (MTT) assay. The results showed that CIP enhanced piezoelectricity and biological performance of the niobate specimen, and also promoted an extracellular matrix‐like topography of it. In vitro studies showed that the CIP‐enhanced material had positive effects on the attachment and proliferation of osteoblasts. Niobate ceramic generated by CIP shows a promise for being a piezoelectric composite bone substitute.
Endosonography for the diagnosis of lymphoma
Authors: Mehrdad Talebian, Bob von Bartheld, Femke Waaijenborg, Jouke Annema
Journal: European Respiratory Journal (2011)

Introduction:  Transesophageal and transbronchial ultrasound-guided fine needle aspiration (EUS-FNA/EBUS-TBNA) are well-established procedures for mediastinal nodal staging of patients with non-small cell lung cancer (NSCLC). Malignant lymphoma often presents with intrathoracic lymph node enlargement. Data on the role of EUS-FNA and EBUS-TBNA for the diagnosis of mediastinal lymphoma are limited.   Objective:  To assess the role of endosonography (EUS-FNA/EBUS-TBNA) for diagnosing mediastinal lymphoma.   Methods:  We retrospectively analyzed 30 patients with suspected (recurrent) lymphoma in which mediastinal lymph nodes were investigated by endosonography using 22-Gauche needles. All patients had a final diagnosis of lymphoma (Hodgkin/Non-Hodgkin lymphoma), based on either surgical procedures, endosonography or clinical follow-up. Sensitivity, specificity and negative predictive value for EUS and EBUS test results were investigated.   Results:  A total of 32 procedures were performed (2 patients underwent both EUS and EBUS). In 13 procedures, aspirates obtained by endosonography demonstrated lymphoma cells. Of these, 12 were true positive and 1 was false positive. Of the other 19 procedures, endosonography findings were true negative in 5 and false negative in 14. Sensitivity, specificity and negative predictive value were 46%, 88% and 26% respectively. No complications occurred.   Conclusion:  EUS-FNA and EBUS-TBNA have moderate sensitivity in diagnosing mediastinal malignant lymphoma. Therefore, negative test results should be followed by surgical staging procedures. Future studies should concentrate on more detailed analysis of cell specific markers on cytology samples (eg flow cytometry) and the use of histology needles.
Prognostic Value of Tumor Architecture, Tumor-Associated Vascular Characteristics, and Expression of Angiogenic Molecules in Pancreatic Endocrine Tumors
Authors: Yu Takahashi, Yuri Akishima-Fukasawa, Noritoshi Kobayashi, Tsuyoshi Sano, Tomoo Kosuge, Yuji Nimura, Yae Kanai, Nobuyoshi Hiraoka
Journal: Clinical Cancer Research (2007)

It is difficult to predict the biological behavior of pancreatic endocrine tumors (PETs). Our aim was to evaluate the prognostic significance of certain variables in PETs.The following variables were examined in 37 patients with PETs and then compared with other clinicopathologic characteristics: histologic tumor structure; microvessel density (MVD) measured by three different methods, including a unique method involving calculation of solid area MVD; endothelial proliferation; and the immunohistochemical expression of vascular endothelial growth factor-A and CXC chemokine CXCL-12. Intratumoral vascular structures were analyzed by double immunofluorescence using 30-microm-thick sections.The presence of focal and intensive solid growth of tumor cells (large solid nests; P = 0.003), low solid area MVD (P = 0.002), a high endothelial cell proliferation index (EPI; P = 0.005), and high expression of CXCL-12 in PET cells (P = 0.018) were significant unfavorable prognostic indicators. The predominant structure of the overall tumor histology and the expression of vascular endothelial growth factor-A did not separate aggressive PETs. In areas of focal solid growth, tumor-associated blood vessels had obviously low MVD and high EPI, and their structures were poorly formed with highly abnormal features, in comparison with other areas. High expression of CXCL-12 in tumor cells was significantly associated with variables representing tumor growth, hematogenous tumor spread, low MVD, high EPI, and the presence of large solid nests.This study has provided novel findings on the prognostic features of tumor architecture and tumor-associated angiogenesis in PETs. CXCL-12 is the first candidate molecule in association with neoangiogenesis in PETs.
Heterogeneous nuclear ribonucleoproteinassociated nucleic acids trigger disease in a rat transfer model of arthritis
Authors: M. Hoffmann, C. W. Steiner, C. Baumann, S. Herman, G. Steiner
Journal: Annals of the Rheumatic Diseases (2010)

Toll-like receptor (TLR)-mediated autoimmunity to nucleic acid-protein complexes has been implicated in the pathogenesis of systemic lupus erythematosus, whereas information regarding the influence of nucleic acid sensing TLRs on the development of rheumatoid arthritis (RA) is scarce. The authors have recently shown that the nucleic acid-binding autoantigen heterogeneous nuclear ribonucleoprotein (hnRNP)-A2 is not …
Lectin-mediated innate defences are important in limiting disease in influenza
Authors: Neelam Kumar
Journal: Thorax (2011)

The innate immune system is an important defence against previously unencountered pathogens. It recognises surface glycans through cell-associated and soluble lectin-mediated defences. This study investigates the effect of blocking these defences on antiviral activities and disease severity in influenza infection.

Mice were infected with two influenza viruses that differ in the degree of glycosylation of …