tbuckley/cabot-search huggingface dataset:
US pharmacists can buy cheap drugs from Canada
Authors: David Spurgeon
Journal: BMJ (2002)

The US Senate has approved a proposal that would allow licensed pharmacists and drug wholesalers to import prescription drugs from Canada that are already approved by the US Food and Drug Administration.

Canadian prices for many drugs range from 25% to 80% lower than those set for the same drugs by the US Congress and the manufacturers. Some US citizens already travel to Canada to buy the drugs or use the internet to import them. This proposal is designed to make it easier for Americans to get access to the drugs.

Writing in the New York Times on 23 June, journalist Robin Toner said that “the fight over prescription drug benefits has become a proxy for the larger struggle over health care itself,” with “millions of elderly struggling to cope, largely on their own, with soaring drug costs.”

Medicare beneficiaries (people aged over 65) spent an average of $813 (£516; €806) of their own money on prescription drugs in 2000 and $928 in 2001 and are spending $1051 in 2002, reports the Kaiser Family Foundation, a health research group. Toner, who visited senior citizens' centres with congressional candidates, says the oldest citizens are among the most vulnerable, with an estimated 45% of those aged 85 or older having no coverage for prescription drugs. Elderly Americans make up 13% of the population but account for 34% of prescriptions.
Results of a phase I study of clofarabine (CLO) plus cyclophosphamide (CY) in adult patients (pts) with relapsed and/or refractory acute lymphoblastic leukemia (ALL)
Authors: S. Faderl, D. A. Thomas, V. Gandhi, X. Huang, G. Borthakur, S. O'Brien, F. Ravandi, W. Plunkett, J. L. Bretz, H. M. Kantarjian
Journal: Journal of Clinical Oncology (2009)

7020 Background: CLO is a second generation nucleoside analog with FDA approval for children with ALL relapse. Single agent CLO in adult ALL was less active so that combinations of CLO with other active agents are pursued. As CLO inhibits DNA repair following exposure to DNA damaging agents, we designed a phase I study of the combination of CLO with CY. Methods: Pts ≥ 21 years (yrs) with primary refractory or relapsed ALL, NYHA class &lt; 3, and a cardiac ejection fraction ≥ 45% were eligible. The continual reassessment method (CRM) was used to determine the maximum tolerated dose (MTD) from 4 pre-defined dose levels. The starting dose level was CLO 40 mg/m 2 i.v. daily x 3d and CY 200 mg/m 2 i.v. q12h x 3d. For cohort 2, CY was 300 mg/m 2 and cohorts 3 and 4 maintained these doses with the treatment duration extended to 4 and 5 days, respectively. Results: Thirty pts have been enrolled. Median age was 28 yrs (range 21–72). Twenty-one pts had pre-B ALL, 5 pts pre-T/T ALL, 1 pt mature B ALL, and 3 pts biphenotypic acute leukemias. Karyotype was diploid in 10 pts and 2 pts had Ph+ ALL. Median number of prior regimens was 2 (1–5). Seven (23%) pts were primary refractory. Among the remainder, preceding median remission duration was 8.6 mos (1–39 mos). Five pts were treated in cohort 1 and 25 in cohort 2. One (20%) pt in cohort 1 and 9 (36%) in cohort 2 experienced DLTs (≥ grade 3) including transaminase elevations, diarrhea, hyperbilirubinemia, and (1 pt each) elevation of creatinine/renal failure, lipase elevation, rash, nausea/vomiting. Evaluable for response were 28 pts: 3 CR (one pt in cohort 1) and 1 marrow CR (OR 14%). All pts had pre-B ALL. One pt had Ph+ ALL, and one was primary refractory to HCVAD. Three early deaths due to infectious complications occurred (all in cohort 2). Conclusions: The MTD for this combination is CLO 40 mg/m 2 i.v. daily x 3d and CY 200 mg/m 2 i.v. q12h x 3d. DLT are mainly GI-related. A phase II extension is ongoing and will focus on efficacy data. [Table: see text]
TCT-12 Short Versus Long-Term Clinical Outcomes In A Randomised Comparison Of Zotarolimus- and Sirolimus-Eluting Coronary Stents
Authors: Michael Maeng, Hans-Henrik Tilsted, Lisette Okkels Jensen, Evald H. Christiansen, Lars Krusell, Jan S. Jensen, Jens Aarøe, Hans Erik Boetker, Anne Kaltoft, Henning Kelbaek, Steen D. Kristensen, Leif Thuesen, Morten Madsen, Henrik T. Soerensen, Anton Villadsen, Per Thayssen, Jan Ravkilde, Jens F. Lassen
Journal: Journal of the American College of Cardiology (2013)
Abstract 14016: Secreted Frizzled Related Protein 2 (Sfrp2) Regulates Resident Cardiac Progenitor Cell Proliferation and Differentiation by Modulating Wnt6 Canonical Signaling
Authors: Jeffrey Schmeckpeper, Farideh Beigi, Alan Payne, Zhiping Zhang, Richard Pratt, Victor J Dzau, Maria Mirotsou
Journal: Circulation (2011)

Introduction: Endogenous repair via activation of cardiac progenitor cells represents an attractive therapeutic approach for limiting remodeling and enhancing cardiac regeneration post infarction. ...
Abstract 3614: Adiponectin Inhibits Vascular Inflammation and Rapid Progression of Atherosclerosis Induced by Angiotensin II
Authors: Joey Liu, Diana Becerra, Rima Boyadjian, Jason Kim, Rajendra K Tangirala
Journal: Circulation (2008)

Adiponectin, an adipocytokine derived from adipose tissue, has anti-inflammatory and antiatherogenic properties and low plasma adiponectin levels are associated with the metabolic syndrome and cardiovascular disease. However, it is unknown whether elevated plasma adiponectin levels provide atheroprotection against angiotensin II (AngII)-induced vascular inflammation and accelerated atherosclerosis. We investigated whether adenoviral adiponectin expression provides protection against AngII-induced inflammation and atherosclerosis. Thirteen week-old low-density lipoprotein receptor-deficient (LDLR −/− ) mice were fed Western diet and infused with Ang-II. Mice were injected with 5 X 10 8 particles of adenovirus expressing either GFP (Ad-GFP, n=16/group) or mouse adiponectin (Ad-APN, n=16/group). Eight weeks after injection, plasma adiponectin levels in Ad-APN-injected mice were increased 12-fold compared to control Ad-GFP mice (306.4 mg/dL vs 25.3 mg/dL). Elevation of plasma adiponectin levels led to a significant increase in plasma HDL levels (23.6% increase vs. control), whereas the plasma cholesterol and triglyceride levels were unchanged. Quantification of atherosclerosis in the entire aortas by en face method, revealed a significant inhibition of atherosclerosis in Ad-APN mice (45% reduction, p&lt;0.01 vs. Ad-GFP mice). Furthermore, adiponectin expression substantially inhibited the mRNA expression of inflammatory and atherogenic genes (ICAM-1, osteopontin, MCP-1 and CCR2) in the vessel wall. Interestingly, adiponectin also increased the mRNA expression of critical reverse cholesterol transport genes, ABCA1 and ABCG1, in the aorta. These results demonstrate that increasing plasma adiponectin levels may be an effective therapeutic strategy to inhibit angiotensin-II induced vascular inflammation and rapid progression of atherosclerosis.
Re: Daniel P. Nguyen, Bashir Al Hussein Al Awamlh, Xian Wu, et al. Recurrence Patterns After Open and Robot-assisted Radical Cystectomy for Bladder Cancer. Eur Urol 2015;68:399–405
Authors: Farshad Pourmalek, Hamidreza Abdi, Peter C. Black
Journal: European Urology (2015)
Abstract 1029: Stromelysin-1 is Critical For Intracranial Bleeding After Tissue-type plasminogen activator Treatment Of Stroke In Mice
Authors: Yasuhiro Suzuki, Nobuo Nagai, Desire Collen, Roger Lijnen, Kazuo Umemura
Journal: Circulation (2007)

Background: Tissue-type plasminogen activator (t-PA) is approved for treatment of ischemic stroke patients, but it may increase the risk of intracranial bleeding (ICB). Matrix metalloproteinases (MMPs), which can be activated through the plasminogen/plasmin system, may contribute to ICB after ischemic stroke. Objectives: To explore the contribution of plasminogen, MMP-3 and MMP-9 to ICB associated with t-PA treatment after ischemic stroke. Methods: Using a thrombotic middle cerebral artery occlusion (MCA-O) model, ICB was studied in mice with genetic deficiencies of plasminogen (Plg −/ − ), stromelysin-1 (MMP-3 −/ − ) or gelatinase B (MMP-9 −/ − ) and their corresponding wild-type (WT) littermates. t-PA (10 mg/kg) or its equivalent volume of solvent was administered intravenously 4 hours after MCA-O. The induction of MMP-3 and MMP-9 was also studied in C57BL/6 WT mice. Results: In MMP-3 +/+ WT mice given solvent, ICB was 4.3 ± 2.9 mm 3 (mean ± SD), which was significantly increased with tPA treatment to 9.7 ± 4.7 mm 3 (P&lt;0.05), whereas ICB in MMP-3 −/ − mice was not altered by t-PA treatment (5.7 ± 2.7 mm 3 , as compared to 5.1 ± 1.8 mm 3 without tPA; n = 7–9 in each group). ICB induced by t-PA was significantly less in Plg −/ − (5.7 ± 3.9 mm 3 ) than in WT mice (8.8 ± 3.2 mm 3 , p&lt;0.05) but ICB by t-PA in MMP-9 −/ − (8.3 ± 2.3 mm 3 ) was comparable with that in WT (8.3 ± 3.1 mm 3 ; n=8 –12 in each group). Administration of the broad-spectrum MMP inhibitor GM6001 after t-PA treatment reduced ICB significantly in MMP-3 +/+ (from 6.4 ± 1.9 mm 3 to 4.1 ± 1.9 mm 3 , p&lt;0.05) but not in MMP-3 −/ − mice (2.2 ± 0.6 mm 3 without versus 2.9 ± 1.5 mm 3 with GM6001; n=6 – 8 in each group). MMP-3 expression was significantly enhanced at the ischemic hemisphere; with placebo treatment, it was expressed only in neurons, whereas it was upregulated in endothelial cells with t-PA treatment. Although MMP-9 expression was also significantly enhanced at the ischemic brain, the amount and the distribution were comparable in mice with and without t-PA treatment. Conclusions: Our data with gene deficient mice suggest that plasminogen and MMP-3 are relatively more important than MMP-9 for the increased ICB induced by t-PA treatment of ischemic stroke.
Analysis of the role of N-cadherin, MCAM, and β3 integrin in the proliferation, migration, and invasion of advanced-stage melanomas
Authors: Kelly Watson, Dorothea Becker
Journal: Cancer Research (2006)

Proc Amer Assoc Cancer Res, Volume 47, 2006

2516 

The cell adhesion molecules N-cadherin, MCAM, and β3 integrin have been postulated to represent melanoma progression markers, and phase I clinical trials currently assess the efficacy of ανβ3 integrin as a therapeutic target for unresectable, locally advanced, or stage IV melanoma. Using whole-genome expression profiling and tissue microarray analysis, we demonstrate expression of the three molecules in the melanoma progression pathway. Since it is presently not known whether targeted inhibition of each adhesion molecule alone suffices to block tumor growth and/or metastasis, or whether expression of all three genes needs to be inhibited simultaneously to block melanoma proliferation, invasion, and metastasis formation, we performed studies, both in vitro and in vivo, to answer this question. We provide evidence that blocking N-cadherin, MCAM, or β3 integrin expression decreases melanoma cell proliferation, yet, blocking their expression in parallel does not augment the anti-proliferative effect. However, blocking N-cadherin, MCAM, andβ3 integrin in concert, inhibits melanoma cell migration and invasion to a significantly greater extent than targeting each gene alone. We further demonstrate that abrogating expression of the three adhesion molecules does not lead to upregulation of other adhesion molecules such as E-cadherin or substantial accumulation of the αv integrin subunit. Taken together, the results of our studies suggest that targeting all three genes at the same time may represent a valuable therapeutic approach for melanoma in its advanced stages.
Insulin-like growth factor receptor signaling pathways and resistance to farnesyl transferase inhibitor SCH66336 (Lonafarnib) in head and neck squamous cell carcinoma
Authors: Seung H. Oh, Waun K. Hong, Ho-Yyoung Lee
Journal: Cancer Research (2006)

Proc Amer Assoc Cancer Res, Volume 47, 2006

1267 

Purpose: The farnesyltransferase inhibitors exhibit antitumor activities in a limited number of cancer cells; however, the mechanism that induces resistance to FTI treatment is still incompletely understood. In this study, we studied the molecular mechanism that interferes with the activities of FTIs, especially [SCH66336][1], in head and neck squamous cell carcinoma (HNSCC) cells. Methods: The effects of [SCH66336][1] and its combination with inhibitors of IGF-1R signaling components on proliferation and apoptosis were assessed in a subset of HNSCC cell lines in vitro by the MTT assay, a flow cytometry-based TUNEL assay, and western blot analyses. The specific role of the survivin in the mechanisms inducing [SCH66336][1] resistance in HNSCC cells were assessed with synthetic small interfering RNAs (siRNA). Results: [SCH66336][1] showed a variable level antiproliferative and apoptotic activities in HNSCC cell lines. We found that [SCH66336][1] suppressed protein expression of survivin, one of the IAP family, and that [SCH66336][1] sensitivity correlated with survivin regulation by the drug. The interference of survivin expression in [SCH66336][1]-insensitive HNSCC cell lines by the transfection with siRNA induced apoptosis in [SCH66336][1]-insensitive HNSCC cell lines. While searching for signaling mechanisms that induce [SCH66336][1]-mediated increase in survivin expression in HNSCC cells, we found that IGF-1R signaling pathway has a major role in controlling survivin expression. In addition, [SCH66336][1] stimulated IGF-1R in [SCH66336][1]-insensitive HNSCC cells. Moreover, combined treatment with [SCH66336][1] and inhibitors of IGFR signaling pathway showed synergistically enhanced antiproliferative effects, which were accompanied by induction of apoptosis. Conclusion: [SCH66336][1] appears to stimulate IGF-IR signaling pathway, which in turn induces survivin expression and resistance to the [SCH66336][1] treatment in HNSCC cells. These results suggest that simultaneous treatment with inhibitors of IGF signaling pathway and [SCH66336][1] might be an effective therapeutic strategy against HNSCC. Supported in by the W81XWH-04-1-0142-01-VITAL from the Department of Defense (to W. K. Hong); National Institutes of Health Grants R01 CA109520-01 (to H-Y. Lee) and CA100816-01A1 (to H-Y. Lee), National American Cancer Society, RSG-04-082-01-TBE 01(to H-Y. Lee)

 [1]: /lookup/external-ref?link_type=GENPEPT&access_num=SCH66336&atom=%2Fcanres%2F66%2F8_Supplement%2F299.3.atom
Rethinking management
Authors: I. H Kunkler
Journal: BMJ (2003)

Editor—Smith in his editorial on the rejection of the proposed consultant contract in England and Wales cites as a principal cause the widespread distrust among clinicians of hospital managers.1 In the same edition, Houghton et al identify a lack of adequate training in writing business plans, negotiating change, and getting things done as specific difficulties for newly appointed consultants.2

Clinicians are often thrust into senior management positions with major responsibilities for substantial budgets without the necessary financial know-how. A fundamental rethink of medical management is called for. What is needed is the development of a distinct career track in medical management at a much earlier stage, with the necessary management training on a par with that available in the commercial sector. This model has worked well in Australia. Such medical managerial posts will need adequate sessional commitments for these managers to provide a high quality of executive function. A professional cadre of medically qualified managers in touch with clinicians involved in the delivery of service, setting realistic targets for service delivery in partnership with lay hospital managers, might restore the trust of the medical profession and deliver the standards of care to which the government aspires.
Induction of apoptosis by 2-methoxy-estradiol in Jurkat cells is associated with topoisomerase II activation
Authors: Christiana Charalambous, Christina Batsi, Evaggelos Kolettas, Andreas Constantinou
Journal: Cancer Research (2007)

3234   2-Methoxy-estradiol (2-ME2), a natural metabolite of 17β-estradiol, was shown to inhibit angiogenesis and the proliferation of many human cancer cells both in vivo and in vitro, but not in normal cells. 2-ME was also shown to induce apoptosis in several tumor cell types through a variety of molecular mechanisms. However, the precise mechanism of action of 2-ME2 remains unknown. In the present study, we examined the role of 2-ME2 in the regulation of apoptosis in human Jurkat T-lymphocytes. Specifically, we investigated the regulation of topoisomerase II (topo II) activity and expression by 2-ME2 as well as the involvement of Bcl-2 in 2-ME2 induced apoptosis of Jurkat cells. We found that 2-ME2 inhibited replication and induced apoptosis of Jurkat cells in a dose and time-dependent manner. Cell cycle protein expression analysis demonstrated that inhibition of cell replication by 2-ME2 was due to the reduction of cyclins D3 and E and the tumor suppressor protein p21 Cip1/Waf1 , and the induction of p16 INK4A . 2-ME2- induced apoptosis was associated with a reduction in expression and phosphorylation (hence inactivation) of Bcl-2, induction of Bak protein expression, activation of caspases 3 and 9 and proteolytic cleavage of PARP. In order to further examine the role of Bcl-2 in 2-ME2 induced Jurkat cell apoptosis and replication, Jurkat cell lines were infected with recombinant retrovectors carrying the puromycin resistance gene with or without human Bcl-2 cDNA and selected with puromycin to generate Jurkat-Puro and Jurkat Bcl-2 cells. 2-ME2 inhibited the replication and induced apoptosis of Jurkat-Puro cells whereas overexpression of Bcl-2 blocked 2-ME2 induced apoptosis of Jurkat cells. In addition, topoisomerase-II activity assays demonstrated that 2-ME2-induced the activation of topo-II in Jurkat and Jurkat-Puro cells but not in Jurkat-Bcl-2 cells. The increase in topo-II activity induced by 2-ME2 correlated with increased phosphorylated topo-II expression in Jurkat and Jurkat-Puro cells but not in Jurkat-Bcl-2 cells. It seems that the increased topo-II activity is at least partly due to the increased levels of phosphorylated topo II. These results taken together suggest that activation of topo-II by 2-ME2 is an important component of the mechanism that leads to apoptosis.   Ackowledgements : Supported by Cyprus Research Promotion Foundation, grant number 0603/25 and General Secretariat of Research and Technology, Ministry of Development in the framework of a Bilateral Agreement between Greece and Cyprus to AC and EK.
Abstract 12438: Effects of Pressure-Overload Induced Left Ventricular Remodeling on Membrane Type-1 Matrix Metalloproteinase Promoter Activation and Expression
Authors: Michael R Zile, Catalin F Baicu, Robert E Stroud, An Van Laer, Rupak Mukherjee, Francis G Spinale
Journal: Circulation (2010)

Background: Pressure-overload causes left ventricular (LV) remodeling with one of the structural milestones of this process being extracellular matrix remodeling and fibrosis. While the regulation of matrix metalloproteinases (MMPs) likely plays a role in this process, the induction and mechanistic role of specific MMPs is poorly understood. Recent in-vivo studies have suggested that the transmembrane MMP, MT1-MMP can actually induce a profibrotic process and thereby effect matrix remodeling and fibrosis in PO. This study tested the hypothesis that in-vivo induction of MT1-promoter activity and expression occurs with PO. Methods: MT1-MMP promoter activity (MT1-PROM act) was measured by generating a transgenic mouse (FVB; full length human MT1-MMP promoter ligated to the firefly luciferase gene). MT1-MMP PROM reporter mice underwent PO (4 weeks transverse aortic constriction n = 13) and were compared to non-banded controls (n = 10). In-vivo MT1-PROM act was quantified by luciferase mRNA expression. LV echo...
Cytokine and Antioxidant Regulation in the Intestine of the Gray Mouse Lemur (Microcebus murinus) During Torpor
Authors: Shannon N. Tessier, Barbara A. Katzenback, Fabien Pifferi, Martine Perret, Kenneth B. Storey
Journal: Genomics Proteomics & Bioinformatics (2015)

Abstract During food shortages, the gray mouse lemur (Microcebus murinus) of Madagascar experiences daily torpor thereby reducing energy expenditures. The present study aimed to understand the impacts of torpor on the immune system and antioxidant response in the gut of these animals. This interaction may be of critical importance given the trade-off between the energetically costly immune response and the need to defend against pathogen entry during hypometabolism. The protein levels of cytokines and antioxidants were measured in the small intestine (duodenum, jejunum, and ileum) and large intestine of aroused and torpid lemurs. While there was a significant decrease of some pro-inflammatory cytokines (IL-6 and TNF-α) in the duodenum and jejunum during torpor as compared to aroused animals, there was no change in anti-inflammatory cytokines. We observed decreased levels of cytokines (IL-12p70 and M-CSF), and several chemokines (MCP-1 and MIP-2) but an increase in MIP-1α in the jejunum of the torpid animals. In addition, we evaluated antioxidant response by examining the protein levels of antioxidant enzymes and total antioxidant capacity provided by metabolites such as glutathione (and others). Our results indicated that levels of antioxidant enzymes did not change between torpor and aroused states, although antioxidant capacity was significantly higher in the ileum during torpor. These data suggest a suppression of the immune response, likely as an energy conservation measure, and a limited role of antioxidant defenses in supporting torpor in lemur intestine.
Disseminated Zoster
Authors: Rachelle M Beste, M Fernanda Bellolio
Journal: New England Journal of Medicine (2015)

A healthy 57-year-old man presented to the emergency department with pain in the left side of the face, a burning sensation on the tongue, and a diffuse vesiculopapular rash involving the chest, back, and bilateral extremities. He reported having had chickenpox as a child.
Suicidal ideation and suicide attempts in panic disorder and social phobia
Authors: B J Cox, D M Direnfeld, R P Swinson, G R Norton
Journal: American Journal of Psychiatry (1994)

Using the original National Institute of Mental Health Epidemiologic Catchment Area (ECA) suicide questions in a clinical setting and including a comparison group of patients with social phobia, the authors attempted to replicate the finding of Weissman and associates of a greater risk of suicidal ideation and suicide attempts associated with panic disorder.One hundred six patients with panic disorder and 41 patients with social phobia answered the five ECA suicide questions and completed a psychometric assessment package at an anxiety disorders clinic.Thirty-three (31%) of the patients with panic disorder and 14 (34%) of the patients with social phobia reported suicidal ideation in the past year, but only one of the patients with panic disorder and two of the patients with social phobia actually made suicide attempts in the past year. Nineteen (18%) of the patients with panic disorder and five (12%) of the patients with social phobia reported making suicide attempts at other times in their lives. Patients who had made past suicide attempts were significantly more likely to report previous psychiatric hospitalizations and past treatment for depression than were patients who had never attempted suicide.These results are consistent with the findings of Weissman and associates that a large proportion of individuals with panic disorder report suicidal ideation. However, many patients with social phobia also reported suicidal ideation, and few individuals in either diagnostic group had actually made recent suicide attempts. Although 12%-18% of the patients reported lifetime suicide attempts, there is evidence to suggest that these were in the context of depressive symptoms.