tbuckley/cabot-search huggingface dataset:
Novel Thioredoxin Inhibitors Paradoxically Increase Hypoxia-Inducible Factor-α Expression but Decrease Functional Transcriptional Activity, DNA Binding, and Degradation
Authors: Dylan T. Jones, Christopher W. Pugh, Simon Wigfield, Malcolm F.G. Stevens, Adrian L. Harris
Journal: Clinical Cancer Research (2006)

Abstract Purpose: Hypoxia-inducible factor-α (HIF-α) is a transcription factor that regulates the response to hypoxia. HIF-α protein is found at high levels in many cancers, and the redox protein thioredoxin-1 (Trx-1) increases both aerobic and hypoxia-induced HIF-α. Therefore, Trx-1 and HIF-α are attractive molecular targets for novel cancer therapeutics. Experimental Design: We investigated whether two novel anticancer drugs AJM290 and AW464 (quinols), which inhibit Trx-1 function, can inhibit the HIF pathway. Results: Treatment of several cancer cell lines with AJM290 or AW464 prevented the hypoxia-induced increase of vascular endothelial growth factor (VEGF) at subtoxic concentrations. AJM290 and AW464 also decreased VEGF in pVHL mutant renal cell carcinoma cells that constitutively overexpress HIF-α protein. They surprisingly up-regulated HIF-α expression in breast cancer cell lines in normoxia and hypoxia as well as in pVHL mutant cells. In the MDA-MB-468 breast cancer cell line, the compounds inhibited RNA and protein expression of the HIF-α target genes, carbonic anhydrase IX, VEGF, and BNIP3, concordantly with HIF-α up-regulation. Both compounds specifically inhibited HIF-α-dependent induction of hypoxia regulatory element-luciferase and HIF-1α hypoxia regulatory element-DNA binding. To analyze the HIF-1α domain inhibited by AJM290, we transfected cells with plasmids expressing a fusion protein of Gal linked to HIF-1α or HIF-1α COOH-terminal transactivation domain (CAD) with a Gal4-responsive luciferase reporter gene. AJM290 inhibited both the full-length HIF-1α and HIF-1α CAD transcriptional activity. Conclusions: AJM290 and AW464 are inhibitors of HIF-1α CAD transcription activity and DNA binding, but they also inhibit degradation of HIF, in contrast to other Trx inhibitors.
Identification of a Major Epitope Recognized by PLA2R Autoantibodies in Primary Membranous Nephropathy
Authors: Maryline Fresquet, Thomas A. Jowitt, Jennet Gummadova, Richard Collins, Ronan O’Cualain, Edward A. McKenzie, Rachel Lennon, Paul E. Brenchley
Journal: Journal of the American Society of Nephrology (2014)

Phospholipase A2 receptor 1 (PLA2R) is a target autoantigen in 70% of patients with idiopathic membranous nephropathy. We describe the location of a major epitope in the N-terminal cysteine-rich ricin domain of PLA2R that is recognized by 90% of human anti-PLA2R autoantibodies. The epitope was sensitive to reduction and SDS denaturation in the isolated ricin domain and the larger fragment containing the ricin, fibronectin type II, first and second C-type lectin domains (CTLD). However, in nondenaturing conditions the epitope was protected against reduction in larger fragments, including the full-length extracellular region of PLA2R. To determine the composition of the epitope, we isolated immunoreactive tryptic fragments by Western blotting and analyzed them by mass spectrometry. The identified peptides were tested as inhibitors of autoantibody binding to PLA2R by surface plasmon resonance. Two peptides from the ricin domain showed strong inhibition, with a longer sequence covering both peptides (31-mer) producing 85% inhibition of autoantibody binding to PLA2R. Anti-PLA2R antibody directly bound this 31-mer peptide under nondenaturing conditions and binding was sensitive to reduction. Analysis of PLA2R and the PLA2R-anti-PLA2R complex using electron microscopy and homology-based representations allowed us to generate a structural model of this major epitope and its antibody binding site, which is independent of pH-induced conformational change in PLA2R. Identification of this major PLA2R epitope will enable further therapeutic advances for patients with idiopathic membranous nephropathy, including antibody inhibition therapy and immunoadsorption of circulating autoantibodies.
PCTs should live beyond 2013 to help GP consortiums bed in, says Nuffield trust
Authors: A. O'Dowd
Journal: BMJ (2011)

Primary care trusts should carry on beyond 2013 to help the new GP commissioning consortiums to develop and offer them strategic guidance, claims a leading health policy think tank.

The Nuffield Trust, which published its response to the government’s listening exercise on English NHS reforms on 27 May, said there was a strong argument to keep primary care trusts (PCTs) despite plans for them to be abolished by April 2013.

It also urged existing disagreements surrounding the Health and Social Care Bill, which will reform the NHS, to be settled quickly so that clinicians, managers, and political leaders could focus on the challenge of meeting financial pressures on the NHS, which has to …
Predictive factors for regression of gastric MALT lymphoma after anti-Helicobacter pylori treatment
Authors: A Ruskone-Fourmestraux
Journal: Gut (2001)

<h3>BACKGROUND AND AIMS</h3> Discrepant remission rates (41–100%) have been reported for patients with localised low grade gastric mucosa associated lymphoid tissue (MALT) lymphoma after eradication of<i>Helicobacter pylori</i>. The aim of this study was to explain these discrepancies and to determine the predictive factors of gastric lymphoma regression after anti- <i>H pylori </i>treatment. <h3>PATIENTS AND METHODS</h3> Forty six consecutive patients with localised gastric MALT lymphoma (Ann Arbor stages I<sub>E</sub> and II<sub>E</sub>) were prospectively enrolled. All had gastric endoscopic ultrasonography and <i>H pylori</i>status assessment (histology, culture, polymerase chain reaction, and serology). After anti-<i>H pylori </i>treatment, patients were re-examined every four months. <h3>RESULTS</h3> Histological regression of the lymphoma was complete in 19/44 patients (43%) (two lost to follow up). Median follow up time for these 19 responders was 35 months (range 10–47). No regression was noted in the 10<i>H pylori</i> negative patients. Among the 34<i>H pylori</i> positive patients, the<i>H pylori</i> eradication rate was 100%; complete regression rate of the lymphoma increased from 56% (19/34) to 79% (19/24) when there was no nodal involvement at endoscopic ultrasonography. There was a significant difference between the response of the lymphoma restricted to the mucosa and other more deep seated lesions (p&lt;0.006). However, using multivariate analysis, the only predictive factor of regression was the absence of nodal involvement (p&lt;0.0001). <h3>CONCLUSION</h3> In<i>H pylori</i> positive patients with localised gastric MALT lymphoma, carefully evaluated and treated without any lymph node involvement assessed by endoscopic ultrasonography, complete remission of lymphoma was reached in 79% of cases.
Comparison of alveolar nitric oxide concentrations using two different methods for the assessment of small airways inflammation in asthma
Authors: Daiki Kobayashi, Yoshihiro Tochino, Hiroshi Kanazawa, Yukikazu Ichimaru, Kyoh Shigenori, Kazuhisa Asai, Kazuto Hirata
Journal: European Respiratory Journal (2011)

Background and objectives: Fractional exhaled nitric oxide (FENO) is considered a potentially useful biomarker to detect airway inflammation. Two-compartment model (2CM) of pulmonary NO dynamics has been used for the evaluation of bronchial NO flux (J'awNO) and peripheral airway/alveolar NO concentration (CANO) in asthmatic patients. Recently, the trumpet shape of airway tree and axial diffusion model (TMAD) has been reported as the correction of 2CM. This study was designed to determine the validity of measurement of CANO using the TMAD model for the assessment of small airways obstruction in asthma

Methods: A total of 52 asthmatic patients and 12 normal controls were included in this study. Methacholine inhalation challenge testing, pulmonary function tests, sputum induction, and exhaled NO measurements at several flow rates were performed. And then J'awNO and CANO were calculated using both the 2CM (CANO 2CM, J'awNO 2CM) and the TMAD model (CANO TMAD, J'awNO TMAD) respectively.

Results: Both J'awNO and CANO were significantly higher in asthmatic patients than normal controls. CANO 2CM was significantly correlated with FEV1/FVC (r=-0.35, p=0.01), FEF25-75 (r=-0.45, p<0.001), and sputum eosinophils (r=0.32, p=0.02). In contrast, CANO TMAD was significantly correlated with FEF25-75 alone (r=-0.42, p=0.002), and not with FEV1/FVC or sputum eosinophils.

Conclusions: CANO TMAD is more selective as an indicator of small airways obstruction than CANO 2CM. Assessment of small airways obstruction using the TMAD model may reveal the role of the small airways in the pathogenesis of asthma.
P-Cadherin Overexpression Is an Indicator of Clinical Outcome in Invasive Breast Carcinomas and Is Associated with <i>CDH3</i> Promoter Hypomethylation
Authors: Joana Paredes, André Albergaria, João T. Oliveira, Carmen Jerónimo, Fernanda Milanezi, Fernando C. Schmitt
Journal: Clinical Cancer Research (2005)

Abstract Purpose: P-cadherin overexpression has been reported in breast carcinomas, where it was associated with proliferative high-grade histological tumors. This study aimed to analyze P-cadherin expression in invasive breast cancer and to correlate it with tumor markers, pathologic features, and patient survival. Another purpose was to evaluate the P-cadherin promoter methylation pattern as the molecular mechanism underlying this gene regulation. Experimental Design: Using a series of invasive breast carcinomas, P-cadherin expression was evaluated and correlated with histologic grade, estrogen receptor, MIB-1, and p53 and c-erbB-2 expression. In order to assess whether P-cadherin expression was associated with changes in CDH3 promoter methylation, we studied the methylation status of a gene 5′-flanking region in these same carcinomas. This analysis was also done for normal tissue and for a breast cancer cell line treated with a demethylating agent. Results: P-cadherin expression showed a strong correlation with high histologic grade, increased proliferation, c-erbB-2 and p53 expression, lack of estrogen receptor, and poor patient survival. This overexpression can be regulated by gene promoter methylation because the 5-Aza-2′-deoxycytidine treatment of MCF-7/AZ cells increased P-cadherin mRNA and protein levels. Additionally, we found that 71% of P-cadherin-negative cases showed promoter methylation, whereas 65% of positive ones were unmethylated (P = 0.005). The normal P-cadherin-negative breast epithelial cells showed consistent CDH3 promoter methylation. Conclusions: P-cadherin expression was strongly associated with tumor aggressiveness, being a good indicator of clinical outcome. Moreover, the aberrant expression of P-cadherin in breast cancer might be regulated by gene promoter hypomethylation.
Stimulant-Induced Enhanced Sexual Desire as a Potential Contributing Factor in HIV Transmission
Authors: Nora D Volkow, Gene-Jack Wang, Joanna S Fowler, Frank Telang, Millard Jayne, Christopher Wong
Journal: American Journal of Psychiatry (2007)

Stimulant abuse is associated with an increased risk of contracting human immunodeficiency virus (HIV). Although sharing of contaminated needles is one of the routes by which HIV is spread, noninjection abusers are also at high risk. The authors investigated the effect of the stimulant drug methylphenidate (given intravenously) on sexual desire as a possible contributing factor to risky sexual behavior associated with the contraction of HIV.The effects of intravenous methylphenidate (0.5 mg/kg) on self-reports of sexual desire (rated from 0-10) were evaluated in 39 comparison subjects and 39 cocaine abusers.Intravenous methylphenidate significantly increased self-reports of sexual desire in comparison subjects (1.4 versus 3.7) and cocaine abusers (2.8 versus 4.8).Stimulant-induced enhancement of sexual desire could be one mechanism by which stimulant drugs such as cocaine and methamphetamine increase the risk for HIV transmission even when they are not injected.
Analysis of deaths occurring within the Nottingham trial of faecal occult blood screening for colorectal cancer
Authors: R. Oliphant, P. McLoone, D. Morrison
Journal: Gut (2010)

We read with interest the analysis of deaths occurring within the Nottingham trial of faecal occult blood screening for colorectal cancer performed by Whynes and colleagues,1 reported in a recent issue of Gut . While the aims of this study are to be commended, we have some concerns regarding the interpretation of ages at death and the methodology used to assign deprivation score.

With respect to age at death, ‘those who participated in screening died at a more advanced age than the controls who, …
Metabolic Response to Infection
Authors: W R Beisel
Journal: Annual Review of Medicine (1975)

A generalized infectious process leads to a broad and complex array of metabolic responses within the host. Certain of these responses have a direct causal relationship to the interactions of body cells with invading microorganisms or their products, or to specific host defensive mechanisms. Other host metabolic responses have less clearly defined roles although they involve many tissues and seem to be initiated and regulated by certain hormones-like endogenous mediators. These latter responses contribute to the maintenance of body homeostasis, the provision of metabolizable energy to meet increased body needs, and the synthesis of the acute phase reactant serum proteins.
Location, Location, Location-Makes All the Difference for Hypoxia in Lung Tumors
Authors: Amit Maity, Constantinos Koumenis
Journal: Clinical Cancer Research (2010)

Hypoxia is a clinically important component of the tumor microenvironment because it adversely affects progression, metastasis, response to chemoradiation therapy, and overall patient survival. Here, we describe how different animal tumor models of lung cancer can yield surprisingly different hypoxic profiles.
Quantification of Colorectal Cancer Micrometastases in Lymph Nodes by Nested and Real-Time Reverse Transcriptase-PCR Analysis for Carcinoembryonic Antigen
Authors: Samuel B. Ho, Ann Hyslop, Richard Albrecht, Amanda Jacobson, Michael Spencer, David A. Rothenberger, Gloria A. Niehans, John D’Cunha, Robert A. Kratzke
Journal: Clinical Cancer Research (2004)

Abstract Purpose: Reverse-transcriptase PCR (RT-PCR) assays for carcinoembryonic antigen (CEA) have been described to identify lymph node micrometastases. These assays are not quantitative and can be confounded by false-positive results. The purpose of this study was to determine whether quantification of CEA in lymph nodes could more readily identify clinically relevant groups. Experimental Design: Specimens included 400 lymph nodes from 64 patients undergoing colon resections. Specimens were tested by immunohistochemistry and by RT-PCR using nested primers for CEA. Specimens from 59 patients that were positive by nested RT-PCR were further quantified by detection of CEA mRNA fluorescence increase at a threshold PCR cycle. Results: CEA was detected by nested RT-PCR analysis in 4 of 34 (12%) nodes of nonneoplastic disease, 2 of 13 (15%) nodes from T1N0 patients, 32 of 81 (40%) nodes of T2N0 patients, 49 of 109 (45%) nodes from T3N0 patients, and 92 of 163 (56%) nodes from T1–4N1–2 patients. The overall presence of any RT-PCR–detectable CEA in nodes did not differentiate patient groups. Immunohistochemistry was positive in nodes from 7% of T3N0 patients and 100% of T1–3N1–2 patients. CEA quantification revealed that 0 of 7 patients with nonneoplastic disease and 2 of 17 (12%) patients with stage I T1–2N0 cancers had one or more lymph nodes with ≥1.0 × 102 CEA transcripts per sample. In contrast, 4 of 13 (31%) patients with stage II T3N0 cancer and 10 of 22 (45%) stage III patients with known metastases had lymph nodes with ≥1.0 × 102 CEA transcripts. Conclusions: These data suggest that quantification of CEA levels in lymph nodes may more accurately identify patients at risk for cancer recurrence than does routine nested RT-PCR or immunohistochemistry.
Induction of T Regulatory Cells Attenuates Idiopathic Nephrotic Syndrome
Authors: Ludmilla Le Berre, Sarah Bruneau, Jeanne Naulet, Karine Renaudin, Françoise Buzelin, Claire Usal, Helga Smit, Thomas Condamine, Jean-Paul Soulillou, Jacques Dantal
Journal: Journal of the American Society of Nephrology (2008)

Buffalo/Mna rats spontaneously develop FSGS and nephrotic syndrome as a result of an immune disorder. Similar to some humans with FSGS, the disease recurs after renal transplantation, suggesting the involvement of a circulating factor. Here, we tested the effect of several immunosuppressive treatments on these rats. Although corticosteroids, cyclosporin A, and anti–T cell receptor treatment reduced proteinuria, only the deoxyspergualin derivative LF15-0195 led to a rapid and complete normalization of proteinuria. Furthermore, this compound led to the regression of renal lesions during both the initial disease and posttransplantation recurrence. The frequency of splenic and peripheral CD4+CD25+FoxP3+ T lymphocytes significantly increased with remission. Moreover, the transfer of purified LF15-0195–induced CD4+CD25+ T cells to irradiated Buff/Mna rats significantly reduced their proteinuria compared with the transfer of untreated control cells, suggesting that LF15-0195 induces regulatory T cells that are able to induce regression of rat nephropathy. These data suggest that idiopathic nephrotic syndrome/FSGS disease can be regulated by cellular transfer, but how this regulation leads to the reorganization of the podocyte cytoskeleton remains to be determined.
Ulcerative colitis complicating seronegative HLA-A2-B27 rheumatoid arthritis with sacroiliitis.
Authors: T Klausen, K Amris, P Helin
Journal: Annals of the Rheumatic Diseases (1992)

The case is reported of a 50 year old man with longstanding seronegative rheumatoid arthritis who developed ulcerative colitis. The patient also had sacroiliitis and his tissue was typed as HLA-A2-B27 several years before the bowel disease began. A possible overlap between primary inflammatory bowel disease, complications to the treatment of rheumatoid arthritis with drugs, and gastrointestinal rheumatoid vasculitis is discussed.
Wnt5A Regulates Expression of Tumor-Associated Antigens in Melanoma via Changes in Signal Transducers and Activators of Transcription 3 Phosphorylation
Authors: Samudra K. Dissanayake, Purevdorj B. Olkhanud, Michael P. O'Connell, Arnell Carter, Amanda D. French, Tura C. Camilli, Chineye D. Emeche, Kyle J. Hewitt, Devin T. Rosenthal, Poloko D. Leotlela, Michael S. Wade, Sherry W. Yang, Larry Brant, Brian J. Nickoloff, Jane L. Messina, Arya Biragyn, Keith S. Hoek, Dennis D. Taub, Dan L. Longo, Vernon K. Sondak, Stephen M. Hewitt, Ashani T. Weeraratna
Journal: Cancer Research (2008)

Abstract There are currently no effective therapies for metastatic melanoma and targeted immunotherapy results in the remission of only a very small percentage of tumors. In this study, we show that the noncanonical Wnt ligand, Wnt5A, can increase melanoma metastasis in vivo while down-regulating the expression of tumor-associated antigens important in eliciting CTL responses (e.g., MART-1, GP100, and tyrosinase). Melanosomal antigen expression is governed by MITF, PAX3, and SOX10 and is inhibited upon signal transducers and activators of transcription 3 (STAT3) activation, via decreases in PAX3 and subsequently MITF expression. Increasing Wnt5A in Wnt5A-low cells activated STAT3, and STAT3 was decreased upon Wnt5A knockdown. Downstream targets such as PAX3, MITF, and MART-1 were also affected by Wnt5A treatment or knockdown. Staining of a melanoma tissue array also highlighted the inverse relationship between MART-1 and Wnt5A expression. PKC activation by phorbol ester mimicked Wnt5A effects, and Wnt5A treatment in the presence of STAT3 or PKC inhibitors did not lower MART-1 levels. CTL activation studies showed that increases in Wnt5A correspond to decreased CTL activation and vice versa, suggesting that targeting Wnt5A before immunotherapy may lead to the enhancement of current targeted immunotherapy for patients with metastatic melanoma. [Cancer Res 2008;68(24):10205–14]
Pulmonary endocrine cells immunoreactive for calcitonin in the lungs of fetal and neonatal rats.
Authors: M C Sissons, J R Gosney
Journal: Thorax (1985)

Previous studies have shown that the size of the population of bronchopulmonary endocrine (Feyrter) cells appears to be greatest in fetal and neonatal life. This has led to the logical assumption that these cells are important during this period and undergo a subsequent decline in number thereafter. In this study endocrine cells containing calcitonin or a closely related cross reacting peptide have been demonstrated in the lungs of fetal and neonatal rats by immunoenzyme histochemistry. They appear first about three days before birth and their number, expressed as immunoreactive cells per cm2 of histological section, remains relatively constant for up to three weeks after birth. It has been shown previously in this department that endocrine cells immunoreactive for calcitonin are present in the lungs of the normal adult rat. Their number in these adult animals is closely similar to the numbers of cells in the lungs of the developing animals of the present study. It is suggested that, at least in the rat, bronchopulmonary endocrine cells immunoreactive for calcitonin have a role that is not confined merely to the period of transition from fetal to neonatal life.
Enalapril Decreases the Incidence of Atrial Fibrillation in Patients With Left Ventricular Dysfunction
Authors: Emmanuelle Vermes, Jean-Claude Tardif, Martial G. Bourassa, Normand Racine, Sylvie Levesque, Michel White, Peter G. Guerra, Anique Ducharme
Journal: Circulation (2003)

Atrial fibrillation (AF) is frequently encountered in patients with heart failure (HF) and is also a predictor of morbidity and mortality in this population. Recent experimental studies have shown electrical and structural atrial remodeling with increased fibrosis in animals with HF and have suggested a preventive effect of ACE inhibitors (ACEi) on the development of AF. To verify the hypothesis that ACEi prevent the development of AF in patients with HF, we conducted a retrospective analysis of the patients from the Montreal Heart Institute (MHI) included in the Studies Of Left Ventricular Dysfunction (SOLVD).Clinical charts were reviewed and serial ECGs interpreted by a single cardiologist blinded to drug allocation. Patients with AF or flutter on the baseline ECG were excluded. Baseline characteristics were obtained from the SOLVD databases. The mean follow-up was 2.9+/-1.0 years. Of the 391 patients randomly assigned at MHI, 374 were in sinus rhythm at the time of random assignment, with 186 taking enalapril and 188 taking placebo. Baseline characteristics were similar in the two groups except for a higher incidence of previous myocardial infarction in the enalapril group. Fifty-five patients had AF during the follow-up: 10 (5.4%) in the enalapril group and 45 (24%) in the placebo group (P<0.0001). By Cox multivariate analysis, enalapril was the most powerful predictor for risk reduction of AF (hazard ratio, 0.22; 95% CI, 0.11 to 0.44; P<0.0001).Treatment with the ACEi enalapril markedly reduces the risk of development of atrial fibrillation in patients with left ventricular dysfunction.