tbuckley/cabot-search huggingface dataset:
Abstract P1-05-13: CLIC3 is associated with invasive behaviour and poorer prognosis in estrogen receptor-negative breast cancer.
Authors: IR Macpherson, M Dozynkiewicz, G Kalna, C Speirs, S Chaudhary, J Edwards, P Timpson, J Norman
Journal: Cancer Research (2012)

Abstract Background: We previously described a Chloride Intracellular Channel-3 (CLIC3)-dependent recycling pathway which trafficked active integrins from late endosomes to the cell surface and which was required for the migratory and invasive behaviour of A2780 ovarian cancer cells in vitro. We also demonstrated that elevated expression of CLIC3 was associated with poor prognosis in pancreatic cancer. We therefore set out to investigate the role of CLIC3 in breast cancer. Materials and Methods: CLIC3 expression was assessed by immunohistochemistry and the weighted histoscore method in a tissue microarray (TMA) consisting of triplicate cores from 141 patients diagnosed with invasive estrogen receptor (ER)-negative early breast carcinoma between 1995 and 1998. Full clinicopathological and follow-up data were available. Further data were obtained from publicly available gene expression datasets (Desmedt, GSE7390) and Oncomine™. Knockdown of CLIC3 in the ER-ve MDA-MB231 breast cancer cell line was achieved by nucleofection of 2 different siRNA sequences (Dharmacon). Inverse invasion assays measured invasion into a plug of matrigel supplemented with fibronectin over 72 hours whilst organotypic invasion assays measured invasion into a fibroblast-containing collagen matrix over 6 days. Results: CLIC3 mRNA expression was significantly elevated in breast cancer in comparison to normal breast tissue in two independent data sets. High CLIC3 protein levels were associated with significantly shorter breast cancer specific survival (p = 0.026) in a TMA of 141 ER-ve patients. This finding was corroborated by the observation that high CLIC3 mRNA levels were associated with shorter overall survival in 198 patients in the Desmedt dataset (p = 0.038). Transient silencing of CLIC3 expression using two independent siRNA sequences had no effect on proliferation of MDA-MB231 cells but significantly reduced their invasiveness by 46% and 93% respectively in an inverse invasion assay and by 36% and 42% respectively in an organotypic invasion assay. CLIC3 was found to co-localise with Rab7 and LAMP1 in late endosomes/lysosomes in MDA-MB231 cells. Conclusions: Our clinical and in vitro data indicate an important role for CLIC3 in the invasive and metastatic behaviour of some breast cancers. Further work to elucidate molecular mechanisms is underway and will be presented. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P1-05-13.
Association of serum Rituximab (IDEC–C2B8) concentration and anti-tumor response in the treatment of recurrent low-grade or follicular non-Hodgkin’s lymphoma
Authors: N.L. Berinstein, A.J. Grillo-López, C.A. White, I. Bence-Bruckler, D. Maloney, M. Czuczman, D. Green, J. Rosenberg, P. McLaughlin, D. Shen
Journal: Annals of Oncology (1998)
Adjustment of therapy in rheumatoid arthritis on the basis of achievement of stable low disease activity with adalimumab plus methotrexate or methotrexate alone: the randomised controlled OPTIMA trial
Authors: Josef S Smolen, Paul Emery, Roy Fleischmann, Ronald F van Vollenhoven, Karel Pavelka, Patrick Durez, Benoît Guérette, Hartmut Kupper, Laura Redden, Vipin Arora, Arthur Kavanaugh
Journal: The Lancet (2013)
PMO-164 HCV p22 antigen test: serological response and diagnostic advantages: Abstract PMO-164 Table 1
Authors: L Lee, G Perrett, P Howard, D Makanjuola, J Clark
Journal: Gut (2012)

<h3>Introduction</h3> The p22 ELISA stains for part of the nucleocapside of hepatitis C virus (HCV) and has recently become commercially available. The current British Society of Gastroenterology guidelines recommend ELISA towards antibodies against HCV Ab. Only 27% of patients with acute HCV are able to clear the virus,<sup>1</sup> however, early treatment in the acute phase is known to improve outcomes and rates of Sustained Virological Response.<sup>2</sup> This has been advocated in certain subgroups (patients co-infected with HIV or moderate-severe liver disease). This case demonstrates the serological response during an acute hepatitis infection with regards to ALT, HCV Ab, HCV RNA and the new p22 HCV antigen test. <h3>Methods</h3> Sequential blood samples were obtained from a patient with end stage renal failure who developed acute HCV infection while on haemodialysis. Liver function tests, ELISA to antibody to HCV, HCV RNA PCR and antigens to p22 were performed retrospectively. <h3>Results</h3> The p22 ELISA result became positive at an earlier time point before a rise in ALT or the ELISA HCV antibody result. <h3>Conclusion</h3> The p22 ELISA is a robust and reliable test that allows for earlier detection of HCV viraemia. This would be of crucial importance in patient subgroups that need early treatment in the acute phase or in populations where early detection would be required to reduce risk of cross-transmission (eg, haemodialysis units). This test offers several advantages over PCR, which though sensitive, involves complex methodology that makes it unsuitable for diagnostic laboratories. Further investigation would be required to establish the role of treating during the hyper-acute phase, in patients with negative HCV antibody and normal ALT. <h3>Competing interests</h3> None declared. <h3>References</h3> 1. <b>Micallef JM</b>, Kaldor JM, Dore GJ. Spontaneous viral clearance following acute hepatitis C infection: a systematic review of longitudinal studies. <i>J Viral Hepat</i> 2006;<b>13</b>:34–41. 2. <b>Corey KE</b>, Mendez-Navarro J, Gorospe EC, <i>et al.</i> Early treatment improves outcomes in acute hepatitis C virus infection: a meta-analysis. <i>J Viral Hepat</i> 2010;<b>17</b>:201–7.
A Randomized Multicenter Trial Comparing the GlucoWatch Biographer With Standard Glucose Monitoring in Children With Type 1 Diabetes
Authors: H Peter Chase, Roy Beck, William Tamborlane, Bruce Buckingham, Nelly Mauras, Eva Tsalikian, Tim Wysocki, Stuart Weinzimer, Craig Kollman, Katrina Ruedy, Dongyuan Xing
Journal: Diabetes Care (2005)

OBJECTIVE—This study assesses whether use of the GlucoWatch G2 Biographer (GW2B) in addition to standard glucose monitoring lowers HbA1c and reduces hypoglycemia compared with standard glucose monitoring alone. RESEARCH DESIGN AND METHODS—In all, 200 subjects aged 7 to &amp;lt;18 years with type 1 diabetes were randomly assigned at five centers to standard glucose monitoring (usual care) or standard glucose monitoring plus GW2B use for 6 months. Study outcomes included HbA1c values obtained at 6 months and occurrence of severe hypoglycemia. RESULTS—The mean HbA1c at baseline was 8.0% in both groups; at 6 months, HbA1c was 7.9% in the usual care group and 8.1% in the GW2B group (95% CI for mean reduction in the GW2B group compared with the usual care group −0.4 to 0.1%; P = 0.15). A decrease in HbA1c of ≥0.5% was achieved in 21% of the usual care group and 28% of the GW2B group (P = 0.29). Severe hypoglycemia events occurred in 7% of the GW2B group and in 2% of the usual care group (P = 0.10). In the GW2B group, sensor use declined throughout the study from a mean value of 2.1 times/week in the 1st month to 1.5 times/week in the 6th month. Reasons given for declining use included skin irritation (76%), frequent skips (56%), excessive alarms (47%), and inaccurate readings (33%). CONCLUSIONS—Use of the GW2B in addition to standard glucose monitoring did not improve glycemic control or reduce the frequency of severe hypoglycemia. Skin reactions and other problems led to decreasing sensor use over time.
Expression of insulin-like growth factor I by activated hepatic stellate cells reduces fibrogenesis and enhances regeneration after liver injury
Authors: S Sanz
Journal: Gut (2004)

Hepatic stellate cells (HSCs) express alpha-smooth muscle actin (alphaSMA) and acquire a profibrogenic phenotype upon activation by noxious stimuli. Insulin-like growth I (IGF-I) has been shown to stimulate HSCs proliferation in vitro, but it has been reported to reduce liver damage and fibrogenesis when given to cirrhotic rats.The authors used transgenic mice (SMP8-IGF-I) expressing IGF-I under control of alphaSMA promoter to study the influence of IGF-I synthesised by activated HSCs on the recovery from liver injury.The transgene was expressed by HSCs from SMP8-IGF-I mice upon activation in culture and in the livers of these animals after CCl4 challenge. Twenty four hours after administration of CCl4 both transgenic and wild type mice showed similar extensive necrosis and increased levels of serum transaminases. However at 72 hours SMP8-IGF-I mice exhibited lower serum transaminases, reduced hepatic expression of alphaSMA, and improved liver morphology compared with wild type littermates. Remarkably, at this time all eight CCl4 treated wild type mice manifested histological signs of liver necrosis that was severe in six of them, while six out of eight transgenic animals had virtually no necrosis. In SMP8-IGF-I mice robust DNA synthesis occurred earlier than in wild type animals and this was associated with enhanced production of HGF and lower TGFbeta1 mRNA expression in the SMP8-IGF-I group. Moreover, Colalpha1(I) mRNA abundance at 72 hours was reduced in SMP8-IGF-I mice compared with wild type controls.Targeted overexpression of IGF-I by activated HSCs restricts their activation, attenuates fibrogenesis, and accelerates liver regeneration. These effects appear to be mediated in part by upregulation of HGF and downregulation of TGFbeta1. The data indicate that IGF-I can modulate the cytokine response to liver injury facilitating regeneration and reducing fibrosis.
Long-Term Opioid Therapy Reconsidered
Authors: Michael Von Korff, Andrew Kolodny, Richard A. Deyo, Roger Chou
Journal: Annals of Internal Medicine (2011)

In the past 20 years, primary care physicians have greatly increased prescribing of long-term opioid therapy. However, the rise in opioid prescribing has outpaced the evidence regarding this practice. Increased opioid availability has been accompanied by an epidemic of opioid abuse and overdose. The rate of opioid addiction among patients receiving long-term opioid therapy remains unclear, but research suggests that opioid misuse is not rare. Recent studies report increased risks for serious adverse events, including fractures, cardiovascular events, and bowel obstruction, although further research on medical risks is needed. New data indicate that opioid-related risks may increase with dose. From a societal perspective, higher-dose regimens account for the majority of opioids dispensed, so cautious dosing may reduce both diversion potential and patient risks for adverse effects. Limiting long-term opioid therapy to patients for whom it provides decisive benefits could also reduce risks. Given the warning signs and knowledge gaps, greater caution and selectivity are needed in prescribing long-term opioid therapy. Until stronger evidence becomes available, clinicians should err on the side of caution when considering this treatment.
Ejection load changes in aortic stenosis. Observations made after balloon aortic valvuloplasty.
Authors: Y Shim, T G Hampton, C A Straley, J K Harrison, L A Spero, T M Bashore, A D Pasipoularides
Journal: Circulation Research (1992)

To investigate complementarity and competitiveness between the intrinsic and extrinsic components of the total left ventricular systolic load, hemodynamic data from 18 elderly subjects with severe aortic stenosis were analyzed before and after balloon dilation of the stenosed aortic valve. Multisensor micromanometric pressure measurements allowed calculation (simplified Bernoulli equation) of the ejection velocity and aortic input impedance spectra. Despite a 32% increase in the aortic valve area (from 0.56 +/- 0.04 to 0.74 +/- 0.05 cm2 [mean +/- SEM], p &lt; 0.01), the peak left ventricular systolic pressure fell by only 12% (from 189 +/- 10 to 167 +/- 8 mm Hg, p &lt; 0.01). This was accompanied by an increase in the impedance at the same cardiac output. In a subset of patients (n = 9) in whom the peak aortic systolic pressure rose after valvuloplasty (from 115 +/- 10 to 128 +/- 12 mm Hg, p &lt; 0.01), a 40% increase in the aortic valve area was accompanied by a marked increase in the aortic input impedance. In this subset, the steady component of the aortic input impedance increased by 24% (from 960 +/- 96 to 1,188 +/- 134 dyne.sec/ml, p &lt; 0.05), and the characteristic impedance increased by 25% (from 106 +/- 13 to 132 +/- 19 dyne.sec/ml, p &lt; 0.05). Because of an increased aortic impedance acutely following the procedure, the total left ventricular systolic load after balloon dilation of the stenotic valve was only slightly decreased despite a significant increase in aortic valve area. This represents an example of complementarity and competitiveness between the intrinsic and extrinsic components of the total systolic ventricular load. It may explain why improvement in left ventricular performance may be modest acutely following balloon aortic valvuloplasty.
Urinary Albumin Excretion Rate Is Associated With Increased Ambulatory Blood Pressure in Normoalbuminuric Type 2 Diabetic Patients
Authors: Cristiane B. Leitão, Luís H. Canani, Patrícia B. Bolson, Marcel P. Molon, Antônio F. Pinotti, Jorge L. Gross
Journal: Diabetes Care (2005)

To evaluate the 24-h blood pressure profile in normoalbuminuric type 2 diabetic patients.A cross-sectional study was conducted in 90 type 2 diabetic patients with a urinary albumin excretion rate (UAER) <20 microg/min on two occasions, 6 months apart (immunoturbidimetry). Patients underwent clinical and laboratory evaluations. Ambulatory blood pressure monitoring and echocardiograms were also performed.UAER was found to correlate positively with systolic doctor's office blood pressure measurements (r = 0.243, P = 0.021) and ambulatory blood pressure (24 h: r = 0.280, P = 0.008) and left ventricular posterior wall thickness (r = 0.359, P = 0.010). Patients were divided into four groups according to UAER (<5, > or =5-10, > or =10-15, and > or =15-20 microg/min). Systolic blood pressure parameters for the 1st, 2nd, 3rd, and 4th groups, respectively, were 123.0 +/- 10.6, 132.5 +/- 15.0, 139.0 +/- 23.4, and 130.7 +/- 8.0 mmHg for 24-h blood pressure (ANOVA P = 0.004) and 48.4 +/- 6.0, 54.5 +/- 11.2, 58.8 +/- 15.6, and 57.6 +/- 8.0 mmHg for 24-h pulse pressure (ANOVA P = 0.003). A progressive increase in the prevalence of diabetic retinopathy was observed from the 1st to the 4th UAER group: 27.3, 43.8, 45.5, and 66.7% (P = 0.029 for trend).In type 2 diabetic patients, UAER in the normoalbuminuric range is positively associated with systolic ambulatory blood pressure indexes, left ventricular posterior wall thickness, and diabetic retinopathy, suggesting that intensive blood pressure treatment may prevent diabetes complications in these patients.
Decision aids, empowerment, and shared decision making
Authors: I. Hargraves, V. M. Montori
Journal: BMJ (2014)

<h3>Introduction</h3> Endothelial microparticles (EMPs) are released from dysfunctional endothelial cells. We hypothesised that patients with unstable carotid plaque have higher levels of circulating microparticles compared to patients with stable plaques which could be related to a specific cytokine profile. <h3>Methods</h3> Circulating EMPs and inflammatory cytokine levels were measured in seventy patients with significant carotid disease undergoing carotid endarterectomy and 20 healthy controls. Fifty one (73%) patients had symptomatic disease whilst 19 (27%) were asymptomatic. EMPs (CD31<sup>+</sup>/ Annexin V<sup>+ </sup>CD42b<sup>-</sup>) were quantified using flow cytometry. Immunohistological analysis of carotid plaques for CD68<sup>+</sup>, CD206<sup>+</sup> macrophages, TNF-α smooth muscle actin and osteopontin was performed, together with Alizarin red staining for detection of calcific deposits. Bioplex assays were used for cytokine analysis. Plaques were graded according to the American Heart Association plaque scoring system. <h3>Results</h3> Significantly higher EMP levels were observed in symptomatic patients compared to controls, p = 0.01, while no differences were noted in EMP levels in asymptomatic <i>vs </i>controls p = 0.11. The higher EMP levels appeared to associate with the unstable plaques which also had a significantly higher level of CD68<sup>+</sup> macrophages compared to stable plaques (AHA I-IV) and higher circulating levels of Chemokine ligand-9 (CXCL-9) (p &lt; 0.004). Of note, macrophage inhibitory factor (MIF) was among the chemokines that were elevated in the circulation of patients with stable plaques, whether a lack of this factor in unstable plaques has direct effects on phenotype remains to be elucidated. Other factors elevated in patients with stable plaques were IL-16, cutaneous T-cell attracting chemokine (CTACK), and stem-cell growth factor-b (SCGF-b) (p value of 0.05, 0.035 and 0.002 respectively). <h3>Conclusion</h3> Circulatory EMP and specific inflammatory cytokine levels are raised in patients with unstable plaques, while MIF, a potentially protective factor was elevated in serum of patients with stable plaques. These data could have major implications for the development of a diagnostic tool whereby EMPs together with markers of macrophage activity could act in a combined manner as biomarkers of plaque vulnerability and stroke susceptibility.
Putative role of cationic amino acid transporter‐3 in murine liver metabolism
Authors: Ellen I. Closs
Journal: Hepatology (2015)

Potential conflict of interest: Nothing to report. To the Editor: With great interest I read the article by Gu et al., revealing a role of cationic amino acid transporter‐3 (CAT‐3) in the regulation of hepatic fatty acid oxidation in zebrafish through nitric oxide/adenosine monophosphate–activated protein kinase/peroxisome proliferator–activated receptor‐α signaling.1 The authors report that they also knocked down the zebrafish ortholog SLC7A3 (CAT‐3) in mouse liver using adenovirus‐based small interfering RNAs. However, so far, there is no evidence for CAT‐3 expression in mammalian liver, even if such sensitive methods as reverse‐transcription polymerase chain reaction were applied.2 Absence of SLC7A3 transcripts from the liver is also indicated in several databases: EST Profile (National Center for Biotechnology Information), GEO Profile (National Center for Biotechnology Information), Expression Atlas (European Molecular Biology Laboratory‐European Bioinformatics Institute), The Human Protein Atlas, Nextprot (Swiss Institute of Bioinformatics), and Mouse Genome Informatics. The situation in an embryonic cell line such as the human L02 line, also investigated by Gu et al., may be different as CAT‐3 is widely expressed during mammalian embryonic development but has a very restricted expression pattern in adult tissues. I am worried about the specificity of the antibody the authors have used to monitor the efficiency of Slc7a3 knockdown (see their fig. 7D). Unfortunately, standard immunization procedures often fail to raise utilizable antibodies against integral membrane proteins, such as CAT‐3, that exhibit few antigenic epitopes. In addition, migration of integral membrane proteins in sodium dodecyl sulfate–polyacrylamide gel electrophoresis is often unpredictable due to glycosylation and integration of overproportional amounts of sodium dodecyl sulfate. I am thus concerned that the effects observed by Gu and coauthors using adenovirus‐based small interfering RNAs against mouse CAT‐3 are either off‐target effects or the result of CAT‐3 knockdown in nonhepatic tissues. As a consequence of knocking down mouse CAT‐3, the authors observed reduced nitric oxide synthase activity in hepatocytes and attributed this to a lack of arginine available to nitric oxide synthase. However, mouse hepatocytes express large quantities of another cationic amino acid transporter, CAT‐2A.5 Although this is a low‐affinity, high‐capacity transporter, it should be able to provide substrate to nitric oxide synthases that have rather high affinities for arginine. It may therefore be worthwhile to investigate if CAT‐2(A) is involved in the regulation of hepatic fatty acid oxidation.
A phase I and pharmacokinetic study of fixed-dose selenomethionine and irinotecan in solid tumors.
Authors: Marwan G Fakih, Lakshmi Pendyala, Patrick F Smith, Patrick J Creaven, Mary E Reid, Vladimir Badmaev, Rami G Azrak, Joshua D Prey, David Lawrence, Youcef M Rustum
Journal: Clinical Cancer Research (2006)

We conducted a phase I study to determine the maximum tolerated dose (MTD) of irinotecan with fixed, nontoxic high dose of selenomethionine.Selenomethionine was given orally as a single daily dose containing 2,200 mug of elemental selenium (Se) starting 1 week before the first dose of irinotecan. Irinotecan was given i.v. once weekly x 4 every 6 weeks (one cycle). The starting dose of irinotecan was 125 mg/m(2)/wk. Escalation occurred in cohorts of three patients until the MTD was defined. Pharmacokinetic studies were done for selenium and irinotecan and its metabolites.Three of four evaluable patients at dose level 2 of irinotecan (160 mg/m(2)/wk) had a dose-limiting diarrhea. None of the six evaluable patients at dose level 1 (125 mg/m(2)/wk irinotecan) had a dose-limiting toxicity. One patient with history of irinotecan-refractory colon cancer achieved a partial response. The long half-life of selenium resulted in a prolonged accumulation towards steady-state concentrations. No significant changes in the pharmacokinetics of CPT-11, SN-38, or SN-38G were identified; however, the coadministration of selenomethionine significantly reduced the irinotecan biliary index, which has been associated with gastrointestinal toxicity.Selenomethionine at 2,200 mug/d did not allow the safe escalation of irinotecan beyond the previously defined MTD of 125 mg/m(2). None of the patients receiving 125 mg/m(2) of irinotecan had grade >2 diarrhea. Unexpected responses and disease stabilizations were noted in a highly refractory population. Further escalation of selenomethionine is recommended in future trials to achieve defined protective serum concentrations of selenium.