tbuckley/cabot-search huggingface dataset:
Apoptosis: targets in pancreatic cancer.
Authors: Sabine Westphal, Holger Kalthoff
Journal: Molecular Cancer (2003)

Pancreatic adenocarcinoma is characterized by poor prognosis, because of late diagnosis and lack of response to chemo- and/or radiation therapies. Resistance to apoptosis mainly causes this insensitivity to conventional therapies. Apoptosis or programmed cell death is a central regulator of tissue homeostasis. Certain genetic disturbances of apoptotic signaling pathways have been found in carcinomas leading to tumor development and progression. In the past few years, the knowledge about the complex pathways of apoptosis has strongly increased and new therapeutic approaches based on this knowledge are being developed. This review will focus on the role of apoptotic proteins contributing to pancreatic cancer development and progression and will demonstrate possible targets to influence this deadly disease.
Evidence for altered vascular responses to exogenous endothelin-1 in patients with advanced cirrhosis with restoration of the normal vasoconstrictor response following successful liver transplantation
Authors: R B Vaughan
Journal: Gut (2003)

<b>Background and aims:</b> There is evidence that dampened responses to endogenous vasoconstrictors contribute to the hyperdynamic circulation that is characteristic of advanced cirrhosis. The aim of this study was to determine whether there is an altered vascular responsiveness to the endothelium derived constricting factor endothelin-1 (ET-1) in patients with decompensated chronic liver disease which might contribute to this abnormal circulatory state, and whether normal endothelin responses are restored following liver transplantation. <b>Methods:</b> Using forearm plethysmography, we studied the vascular response to an intra-arterial ET-1 infusion in six patients with end stage cirrhosis, before and after liver transplantation, compared with six normal control subjects. Responses to the selective endothelin A (ET<sub>A</sub>) receptor subtype antagonist, BQ123, were also examined. <b>Results:</b> The forearm vessels of patients with cirrhosis vasodilated in response to ET-1 infusion while in healthy controls a marked vasoconstriction response was observed (p&lt;0.0001, area under the curve time-blood flow was normal compared with the cirrhosis groups, ANOVA). Prior to commencement of liver transplant surgery, cirrhotic patients were confirmed to have a hyperdynamic circulation with a high cardiac index (4.07 (0.23) l/min/m<sup>2</sup> (normal range 2.8–3.6 l/min/m<sup>2</sup>)) and low systemic vascular resistance index (1284 (115) dyn×s/cm<sup>5</sup>/m<sup>2</sup> (normal range 1760–2600 dyn×s/cm<sup>5</sup>/m<sup>2</sup>)). Following transplantation, normal vasoconstrictor responses to ET-1 were restored. Responses to BQ123 were not different in patients with advanced cirrhosis compared with controls. <b>Conclusion:</b> In patients with end stage cirrhosis, ET-1 produces vasodilatation at a dose that causes marked vasoconstriction in normal control subjects. This effect is not attributable to impairment of ET<sub>A</sub> receptor responses. Our findings suggest that altered endothelin responses may contribute to the generalised dilatation of the circulation that occurs in patients with advanced liver disease.
BAFF and APRIL: A Tutorial on B Cell Survival
Authors: Fabienne Mackay, Pascal Schneider, Paul Rennert, Jeffrey Browning
Journal: Annual Review of Immunology (2003)

BAFF, a member of the TNF family, is a fundamental survival factor for transitional and mature B cells. BAFF overexpression leads to an expanded B cell compartment and autoimmunity in mice, and elevated amounts of BAFF can be found in the serum of autoimmune patients. APRIL is a related factor that shares receptors with BAFF yet appears to play a different biological role. The BAFF system provides not only potential insight into the development of autoreactive B cells but a relatively simple paradigm to begin considering the balancing act between survival, growth, and death that affects all cells.
Monitoring tuberculosis treatment outcome: analysis of national surveillance data from a clinical perspective
Authors: I C Ditah, M Reacher, C Palmer, J M Watson, J Innes, M E Kruijshaar, H N Luma, I Abubakar
Journal: Thorax (2007)

<h3>Background:</h3> In 1998, the World Health Organization (WHO) and the International Union Against Tuberculosis and Lung Disease (IUATLD) published recommendations standardising the evaluation of tuberculosis treatment outcome in Europe. These guidelines fail to account for clinically appropriate alterations in the management of patients. <h3>Objectives:</h3> To evaluate tuberculosis treatment outcome in England, Wales and Northern Ireland by redefining the outcome criteria and investigate factors associated with unsuccessful treatment outcome 12 months after notification. <h3>Methods:</h3> This was a prospective analysis of a cohort of patients diagnosed in England, Wales and Northern Ireland and reported to the Enhanced Tuberculosis Surveillance system in 2001 and 2002. Proportions of success and failure were calculated based on a new set of criteria following discussion with clinicians treating tuberculosis cases. Logistic regression was used to study risk factors for unsuccessful treatment outcome. <h3>Results:</h3> 13 048 cases were notified in the study period. Of the 2676 that were identified as new sputum smear positive pulmonary cases, 2209 (82.5%) had treatment outcome data reported. Using the WHO/IUATLD criteria, 76.8% were classified as successful. In contrast, applying the new criteria, the success rate was 87.5%. This rate exceeds the 85% success target set by the WHO. Risk factors for unsuccessful treatment outcome included male sex (OR 1.27; 95% CI 1.08 to 1.49), being elderly (p trend &lt;0.001), having pulmonary tuberculosis (OR 1.28; 95% CI 1.08 to 1.53) and having resistance to any antituberculosis drug (OR 1.90; 95% CI 1.44 to 2.52). <h3>Conclusion:</h3> The proportion of tuberculosis cases with a successful treatment outcome exceeded the target of 85% success rate based on the modified outcome categories. Although the tuberculosis treatment outcome criteria set by WHO/IUATLD appear to be clear, they mix measures of process and outcome. Further refinement may be necessary in low incidence high income countries, especially those with a high mortality among the elderly.
Development, dimensions, reliability and validity of the novel Manchester COPD fatigue scale
Authors: K Al-shair, U Kolsum, P Berry, J Smith, A Caress, D Singh, J Vestbo
Journal: Thorax (2009)

<h3>Introduction:</h3> Fatigue is a prominent symptom in chronic obstructive pulmonary disease (COPD) and it has distinctive features; however, there is a need for a robust scale to measure fatigue in COPD. <h3>Methods:</h3> At baseline, 122 patients with COPD (forced expiratory volume in 1 s (FEV<sub>1</sub>) 52%, women 38%, mean age 66 years) completed a pilot fatigue scale covering a pool of 57 items and underwent a range of tests, including indicators of mood and a short general fatigue questionnaire. All patients responded to the 57-item scale and it was readministered to a subset of 30 patients. The pilot scale was first subjected to constructive validated shortening steps and then to a principal components analysis. <h3>Results:</h3> The Manchester COPD fatigue scale (MCFS) consists of 27 items, loading into three dimensions: physical, cognitive and psychosocial fatigue. Internal consistency (Cronbach's α = 0.97) and test–retest repeatability (r = 0.97, p&lt;0.001) were tested. It had significant convergent validity, correlating with the FACIT (Functional Assessment of Chronic Illness Therapy) fatigue scale and the fatigue in Borg scale at baseline and after a 6 minute walk distance (6MWD) test (r = −0.81, 0.53 and 0.63, respectively, p&lt;0.001). Its scores were associated with BODE, SGRQ (St George's Respiratory Questionnaire) and MRC (Medical Research Council) dyspnoea scores (r = 0.46, 0.8 and 0.51, respectively, p&lt;0.001). The scale demonstrated meaningful discriminating ability; patients who walked &lt;350 m in a 6MWD test as well as depressed patients (⩾16 scores in the Center for Epidemiologic Study on Depression (CES-D) scale) had nearly twice as high fatigue scores as those who walked ⩾350 m or were not depressed (p&lt;0.001). <h3>Conclusion:</h3> The MCFS provides a simple, reliable and valid measurement of total and dimensional fatigue in moderate stable COPD.
SPIRIT 2013 Statement: Defining Standard Protocol Items for Clinical Trials
Authors: An-Wen Chan, Jennifer M. Tetzlaff, Douglas G. Altman, Andreas Laupacis, Peter C. Gøtzsche, Karmela Krleža-Jerić, Asbjørn Hróbjartsson, Howard Mann, Kay Dickersin, Jesse A. Berlin, Caroline J. Doré, Wendy R. Parulekar, William S.M. Summerskill, Trish Groves, Kenneth F. Schulz, Harold C. Sox, Frank W. Rockhold, Drummond Rennie, David Moher
Journal: Annals of Internal Medicine (2013)

The protocol of a clinical trial serves as the foundation for study planning, conduct, reporting, and appraisal. However, trial protocols and existing protocol guidelines vary greatly in content and quality. This article describes the systematic development and scope of SPIRIT (Standard Protocol Items: Recommendations for Interventional Trials) 2013, a guideline for the minimum content of a clinical trial protocol. The 33-item SPIRIT checklist applies to protocols for all clinical trials and focuses on content rather than format. The checklist recommends a full description of what is planned; it does not prescribe how to design or conduct a trial. By providing guidance for key content, the SPIRIT recommendations aim to facilitate the drafting of high-quality protocols. Adherence to SPIRIT would also enhance the transparency and completeness of trial protocols for the benefit of investigators, trial participants, patients, sponsors, funders, research ethics committees or institutional review boards, peer reviewers, journals, trial registries, policymakers, regulators, and other key stakeholders.
4-1BB Ligand as an Effective Multifunctional Immunomodulator and Antigen Delivery Vehicle for the Development of Therapeutic Cancer Vaccines
Authors: Rajesh K. Sharma, Rich-Henry Schabowsky, Abhishek K. Srivastava, Kutlu G. Elpek, Shravan Madireddi, Hong Zhao, Zhenping Zhong, Robert W. Miller, Kathryn J. MacLeod, Esma S. Yolcu, Haval Shirwan
Journal: Cancer Research (2010)

Therapeutic subunit vaccines based on tumor-associated antigens (TAA) represent an attractive approach for the treatment of cancer. However, poor immunogenicity of TAAs requires potent adjuvants for therapeutic efficacy. We recently proposed the tumor necrosis factor family costimulatory ligands as potential adjuvants for therapeutic vaccines and, hence, generated a soluble form of 4-1BBL chimeric with streptavidin (SA-4-1BBL) that has pleiotropic effects on cells of innate, adaptive, and regulatory immunity. We herein tested whether these effects can translate into effective cancer immunotherapy when SA-4-1BBL was also used as a vehicle to deliver TAAs in vivo to dendritic cells (DCs) constitutively expressing the 4-1BB receptor. SA-4-1BBL was internalized by DCs upon receptor binding and immunization with biotinylated antigens conjugated to SA-4-1BBL resulted in increased antigen uptake and cross-presentation by DCs, leading to the generation of effective T-cell immune responses. Conjugate vaccines containing human papillomavirus 16 E7 oncoprotein or survivin as a self-TAA had potent therapeutic efficacy against TC-1 cervical and 3LL lung carcinoma tumors, respectively. Therapeutic efficacy of the vaccines was associated with increased CD4(+) T and CD8(+) T-cell effector and memory responses and higher intratumoral CD8(+) T effector/CD4(+)CD25(+)Foxp3(+) T regulatory cell ratio. Thus, potent pleiotropic immune functions of SA-4-1BBL combined with its ability to serve as a vehicle to increase the delivery of antigens to DCs in vivo endow this molecule with the potential to serve as an effective immunomodulatory component of therapeutic vaccines against cancer and chronic infections.
Key questions concerning paracetamol and NSAIDs for osteoarthritis
Authors: P Courtney
Journal: Annals of the Rheumatic Diseases (2002)

Paracetamol has a pivotal role in the pharmacological treatment of symptomatic OA

Expert guidelines from both sides of the Atlantic have consistently recommended paracetamol, not non-steroidal anti-inflammatory drugs (NSAIDs), as the initial oral drug treatment for osteoarthritis (OA).1–5 This has been justified by the excellent safety record and low cost of paracetamol relative to NSAIDs, and the absence of any significant clinical benefit of NSAIDs over simple analgesia. However, recent data from the USA suggest that NSAIDs may be better than paracetamol for symptom relief in large joint (hip, knee) OA.6–8 These data follow shortly after an unprecedentedly high profile launch and promotion of selective inhibitors of cyclo-oxygenase 2 (coxibs). The clinical benefit of coxibs in OA is equivalent to that of traditional NSAIDs, but coxibs do not have the increased risk of severe gastrointestinal (GI) side effects (peptic ulceration, bleeding, perforation, and obstruction). In America, particularly, these events have led to an intense debate about the relative role of NSAIDs, coxibs, and paracetamol in OA management. This review deals with key questions relating to such drug prescribing for the management of OA.

Although guidelines and reviews about the management of OA seem to be obsessed with this question, it probably has little relevance to clinical practice. Many patients treat themselves before consulting any doctor and have tried over the counter medicines that may include both paracetamol and NSAIDs.8 The concept of which drug to use first implies that monotherapy is the norm. However, most clinical trials of NSAIDs and coxibs allow concomitant paracetamol as “escape analgesia” and in a clinical setting a package of care is usually delivered. As rheumatologists largely see patients with OA only once and after a considerable delay, a more pertinent question for them may be “which drug, or drugs, …
MYOCARDIAL PRECONDITIONING PROMISES TO BE A NOVEL APPROACH TO THE TREATMENT OF ISCHEMIC HEART DISEASE
Authors: Michael V. Cohen, M.D, James M. Downey, Ph.D
Journal: Annual Review of Medicine (1996)

▪ Abstract In the phenomenon termed "ischemic preconditioning," a brief period of ischemia prior to a more prolonged one improves myocardial function (after reperfusion) and diminishes infarction. This phenomenon has been described extensively in experimental animals and now in humans. It is triggered by several agents released by ischemic cells and can be reproduced by infusion of agonists coupled to protein kinase C (PKC), e.g. adenosine, angiotensin, phenylephrine, bradykinin, and endothelin. The intracellular signaling pathway involves a phospholipase, either C or D, which metabolizes membrane phospholipids to produce diacylglycerol, a necessary endogenous cofactor for PKC activation. Which protein(s) is phosphorylated by PKC is not yet known, nor is the identity of the end-effector that actually mediates protection of the ischemic cell. Identification of the end-effector may make it possible in the routine treatment of patients with ischemic heart disease to precondition and thereby salvage ischemic myocardium and improve survival.
Allelic polymorphism in the Plasmodium vivax dihydrofolate reductase gene among Indian field isolates
Authors: S.K. Prajapati, H. Joshi, N. Valecha, A.M. Reetha, A. Eapen, A. Kumar, M.K. Das, R.S. Yadav, M.A. Rizvi, A.P. Dash
Journal: Clinical Microbiology and Infection (2006)
Egg Consumption and Risk of Type 2 Diabetes in Men and Women
Authors: Luc Djoussé, J. Michael Gaziano, Julie E. Buring, I-Min Lee
Journal: Diabetes Care (2009)

We would like to thank Drs. Citrome and Holt for their comments (1) on our article published in the February issue of Diabetes Care (2). Drs. Citrome and Holt raised the issue of residual confounding by bacon and hotdogs (frequently consumed with eggs) or our inability to distinguish between fried or boiled eggs. This is of particular concern in men studied, for whom we did not have nutrient data to control for energy intake and trans , saturated, and unsaturated fats. We agree that in the absence of random assignment of egg consumption, we cannot exclude residual confounding as partial or complete explanation of …
Why are hospital admissions of children with acute asthma increasing?
Authors: EA Mitchell, KP Dawson
Journal: European Respiratory Journal (1989)

The hospital admission rate for asthma has increased in many countries. Particularly prominent has been the increase for children, especially male children under five yrs. The increased admission rate refers to increased number of individuals and to increased frequency per individual. The moderate increase in asthma prevalence does not account for the large increase in admissions. Various other factors are discussed here, such as changes in admission criteria, medical management, and/or clinical expression of the disease.
Membrane-Associated and Secreted Genes in Breast Cancer
Authors: Nathan O. Stitziel, Brenton G. Mar, Jie Liang, Carol A. Westbrook
Journal: Cancer Research (2004)

Abstract The identification of membrane-associated and secreted genes that are differentially expressed is a useful step in defining new targets for the diagnosis and treatment of cancer. Extracting information on the subcellular localization of genes represented on DNA microarrays is difficult and is limited by the incomplete sequence and annotation that is available in existing databases. Here we combine a biochemical and bioinformatic approach to identify membrane-associated and secreted genes expressed in the MCF-7 breast cancer cell line. Our approach is based on the analysis of differential hybridization levels of RNAs that have been physically separated by virtue of their association with polysomes on the endoplasmic reticulum. This approach is specifically applicable to oligonucleotide microarrays such as Affymetrix, which use single-color hybridization instead of dual-color competitive hybridizations. Assignment to membrane-associated and secreted class membership is based on both the differential hybridization levels and an expression threshold, which are calculated empirically from data collected on a reference set of known cytoplasmic and membrane proteins. This method enabled the identification of 755 membrane-associated and secreted probe sets expressed in MCF-7 cells for which this annotation did not previously exist. The data were used to filter a previously reported expression dataset to identify membrane-associated and secreted genes which are associated with poor prognosis in breast cancer and represent potential targets for diagnosis and treatment. The approach reported here should provide a useful tool for the analysis of gene expression patterns, identifying membrane-associated or secreted genes with biological relevance that have the potential for clinical applications in diagnosis or treatment.
SDF-1α/CXCR4 Axis Is Instrumental in Neointimal Hyperplasia and Recruitment of Smooth Muscle Progenitor Cells
Authors: Alma Zernecke, Andreas Schober, Ilze Bot, Philipp von Hundelshausen, Elisa A. Liehn, Barbara Möpps, Mathias Mericskay, Peter Gierschik, Erik A. Biessen, Christian Weber
Journal: Circulation Research (2005)

Recent evidence infers a contribution of smooth muscle cell (SMC) progenitors and stromal cell-derived factor (SDF)-1α to neointima formation after arterial injury. Inhibition of plaque area and SMC content in apolipoprotein E-deficient mice repopulated with LacZ + or CXCR4 −/− BM or lentiviral transfer of an antagonist reveals a crucial involvement of local SDF-1α and its receptor CXCR4 in neointimal hyperplasia via recruitment of BM-derived SMC progenitors. After arterial injury, SDF-1α expression in medial SMCs is preceded by apoptosis and inhibited by blocking caspase-dependent apoptosis. SDF-1α binds to platelets at the site of injury, triggers CXCR4- and P-selectin-dependent arrest of progenitor cells on injured arteries or matrix-adherent platelets, preferentially mobilizes and recruits c-kit − /platelet–derived growth factor receptor (PDGFR)-β + /lineage − /sca-1 + progenitors for neointimal SMCs without being required for their differentiation. Hence, the SDF-1α/CXCR4 axis is pivotal for vascular remodeling by recruiting a subset of SMC progenitors in response to apoptosis and in concert with platelets, epitomizing its importance for tissue repair and identifying a prime target to limit lesion development.
451 High prevalence of hepatitis B virus infection in b-cell non-hodgkin lymphoma
Authors: E. Bianco, E. Marcucci, A. Mele, E. Spada, A. Candido, A. Pulsoni, P. Chionne, E. Madonna, R. Cotichini, A. Barbui, A. De Renzoo, E. Iannitto, V. Liso, B. Martino, M. Montanaro, L. Pagano, P. Musto, M. Rapicetta
Journal: Journal of Hepatology (2006)
High Concentrations of AGE-LDL and Oxidized LDL in Circulating Immune Complexes Are Associated With Progression of Retinopathy in Type 1 Diabetes
Authors: Maria F. Lopes-Virella, Nathaniel L. Baker, Kelly J. Hunt, Timothy J. Lyons, Alicia J. Jenkins, Gabriel Virella
Journal: Diabetes Care (2012)

To determine whether immunocomplexes (ICs) containing advanced glycation end product (AGE)-LDL (AGE-LDL) and oxidized LDL (oxLDL) contribute to the development of retinopathy over a 16-year period in subjects with type 1 diabetes.Levels of AGE-LDL and oxLDL in ICs were measured in 517 patients of the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) cohort. Retinopathy was assessed by stereoscopic fundus photography. Cox proportional hazards models were used to assess the effect of AGE-LDL-ICs and oxLDL-ICs on retinopathy progression.In unadjusted models, higher baseline levels of AGE-LDL-ICs and oxLDL-ICs significantly predicted progression of diabetic retinopathy outcomes. After adjustment by study-design variables (treatment group, retinopathy cohort, duration of type 1 diabetes, and baseline albumin excretion rate [AER], hemoglobin A(1c) (HbA(1c)), and Early Treatment Diabetic Retinopathy Study [ETDRS] score), one SD increase in IC levels was associated with 47% (hazard ratio [HR] 1.47 [95% CI 1.19-1.81]; AGE-LDL-IC) and 45% (1.45 [1.17-1.80]; oxLDL-IC) increased risk of developing proliferative diabetic retinopathy (PDR) and 37% (1.37 [1.12-1.66]; to both ICs) increased risk of progressing to severe nonproliferative retinopathy. Analyses were stratified by retinopathy cohort because results differed between primary and secondary cohorts. For AGE-LDL-ICs, HR for progression to PDR was 2.38 (95% CI 1.30-4.34) in the primary cohort and attenuated in the secondary cohort (1.29 [1.03-1.62]). Similar results were observed for oxLDL-ICs.Increased levels of AGE-LDL and oxLDL in ICs are associated with increased risk for progression to advanced retinopathy in patients with type 1 diabetes, indicating that the antibody response to modified LDL plays a significant role in retinopathy progression.