tbuckley/cabot-search huggingface dataset:
A novel ligand delivery system to non-invasively visualize and therapeutically exploit the IL13Rα2 tumor-restricted biomarker
Authors: Van Nguyen, Jesse M. Conyers, Dongqin Zhu, Denise M. Gibo, Roy R. Hantgan, Steven M. Larson, Waldemar Debinski, Akiva Mintz
Journal: Neuro-Oncology (2012)

Our objective was to exploit a novel ligand-based delivery system for targeting diagnostic and therapeutic agents to cancers that express interleukin 13 receptor alpha 2 (IL13Rα2), a tumor-restricted plasma membrane receptor overexpressed in glioblastoma multiforme (GBM), meningiomas, peripheral nerve sheath tumors, and other peripheral tumors. On the basis of our prior work, we designed a novel IL13Rα2-targeted quadruple mutant of IL13 (TQM13) to selectively bind the tumor-restricted IL13Rα2 with high affinity but not significantly interact with the physiologically abundant IL13Rα1/IL4Rα heterodimer that is also expressed in normal brain. We then assessed the in vitro binding profile of TQM13 and its potential to deliver diagnostic and therapeutic radioactivity in vivo. Surface plasmon resonance (SPR; Biacore) binding experiments demonstrated that TQM13 bound strongly to recombinant IL13Rα2 (Kd∼5 nM). In addition, radiolabeled TQM13 specifically bound IL13Rα2-expressing GBM cells and specimens but not normal brain. Of importance, TQM13 did not functionally activate IL13Rα1/IL4Rα in cells or bind to it in SPR binding assays, in contrast to wtIL13. Furthermore, in vivo targeting of systemically delivered radiolabeled TQM13 to IL13Rα2-expressing subcutaneous tumors was demonstrated and confirmed non-invasively for the first time with 124I-TQM13 positron emission tomography imaging. In addition, 131I-TQM13 demonstrated in vivo efficacy against subcutaneous IL13Rα2-expressing GBM tumors and in an orthotopic synergeic IL13Rα2-positive murine glioma model, as evidenced by statistically significant survival advantage. Our results demonstrate that we have successfully generated an optimized biomarker-targeted scaffolding that exhibited specific binding activity toward the tumor-associated IL13Rα2 in vitro and potential to deliver diagnostic and therapeutic payloads in vivo.
A prospective randomized clinical trial of 0.1% tacrolimus ointment in a model of chronic allergic contact dermatitis
Authors: Donald Belsito, David C. Wilson, Erin Warshaw, Joseph Fowler, Alison Ehrlich, Bryan Anderson, Bruce E. Strober, Jennifer Willetts, Edward S. Rutledge
Journal: Journal of the American Academy of Dermatology (2006)
An Early Signal of CA-125 Progression for Ovarian Cancer Patients Receiving Maintenance Treatment After Complete Clinical Response to Primary Therapy
Authors: Ping-Yu Liu, David S. Alberts, Bradley J. Monk, Mark Brady, James Moon, Maurie Markman
Journal: Journal of Clinical Oncology (2007)

For ovarian cancer patients receiving maintenance treatment after complete clinical response to primary therapy, we tested the predictive value of the following early signal of progressive disease (EPD) criterion based on serum CA-125: for patients with CA-125 nadir <or= 10 U/mL, a confirmed value of >or= 20 U/mL serves as an early signal of CA-125 progression; for patients with nadir more than 10 U/mL, a value >or= 2x nadir that is confirmed predicts progression. PATIENTS AND METHODS The EPD criterion was tested on Southwest Oncology Group trial 9701/Gynecologic Oncology Group trial 178 patients (n = 288) and compared with Gynecologic Cancer Intergroup criterion.For 204 patients with known progressive disease, the progression date was predated by EPD by <or= 60 days in 31%, 61 to 180 days in 15%, and more than 180 days in 10% (median, 56 days early). Of 84 progression-free patients, nine EPDs were found. Overall, 135 patients met the EPD criterion. True disease progression status was undeterminable for two patients and nine were potentially false signals, for a conservative positive predictive value of 93% (95% CI, 88% to 97%).Initial testing of the proposed CA-125 criterion resulted in a low false-positive rate and early prediction of disease progression in more than 50% of the patients tested. The proposed criterion may better reflect the timing of disease progression and should be investigated further.
Two fixed-dose artemisinin combinations for drug-resistant falciparum and vivax malaria in Papua, Indonesia: an open-label randomised comparison
Authors: A Ratcliff, H Siswantoro, E Kenangalem, R Maristela, RM Wuwung, F Laihad, EP Ebsworth, NM Anstey, E Tjitra, RN Price
Journal: The Lancet (2007)
Challenges in Systematic Reviews of Economic Analyses
Authors: Michael Pignone
Journal: Annals of Internal Medicine (2005)

Economic analyses can provide valuable information for health care decision makers. Systematic reviews of economic analyses can integrate information from multiple studies and provide important insights by systematically examining how differences between models lead to different results. We use our experience in developing and implementing systematic reviews of economic analyses for the U.S. Preventive Services T ask Force, particularly our systematic review of the cost–effectiveness of colorectal cancer screening, to illustrate key methodologic challenges and suggest a framework for other researchers in this area.
Cost utility analysis of sildenafil compared with papaverine-phentolamine injections
Authors: E. A Stolk
Journal: BMJ (2000)

<h3>Abstract</h3> <b>Objective:</b> To compare the cost effectiveness of sildenafil and papaverine-phentolamine injections for treating erectile dysfunction. <b>Design:</b> Cost utility analysis comparing treatment with sildenafil (allowing a switch to injection therapy)and treatment with papaverine-phentolamine (no switch allowed). Costs and effects were estimated from the societal perspective. Using time trade-off, a sample of the general public (n=169) valued health states relating to erectile dysfunction. These values were used to estimated health related quality of life by converting the clinical outcomes of a trial into quality adjusted life years (QALYs). <b>Participants:</b> 169 residents of Rotterdam. <b>Main outcome measures:</b> Cost per quality adjusted life year. <b>Results:</b> Participants thought that erectile dysfunction limits quality of life considerably: the mean utility gain attributable to sildenafil is 0.11. Overall, treatment with sildenafil gained more QALYs, but the total costs were higher. The incremental cost effectiveness ratiofor the introduction of sildenafil was £3639 in the first year and fell in following years. Doubling the frequency of use of sildenafil almost doubled the cost per additional QALY. <b>Conclusions:</b> Treatment with sildenafil is cost effective. When considering fundingsildenafil, healthcare systems should take into account that the frequency of use affects cost effectiveness.
The clinical impact of bacterial biofilms
Authors: Niels Høiby, Oana Ciofu, Helle Krogh Johansen, Zhi‐jun Song, Claus Moser, Peter Østrup Jensen, Søren Molin, Michael Givskov, Tim Tolker‐Nielsen, Thomas Bjarnsholt
Journal: International Journal of Oral Science (2011)

Bacteria survive in nature by forming biofilms on surfaces and probably most, if not all, bacteria (and fungi) are capable of forming biofilms. A biofilm is a structured consortium of bacteria embedded in a self-produced polymer matrix consisting of polysaccharide, protein and extracellular DNA. Bacterial biofilms are resistant to antibiotics, disinfectant chemicals and to phagocytosis and other components of the innate and adaptive inflammatory defense system of the body. It is known, for example, that persistence of staphylococcal infections related to foreign bodies is due to biofilm formation. Likewise, chronic Pseudomonas aeruginosa lung infections in cystic fibrosis patients are caused by biofilm growing mucoid strains. Gradients of nutrients and oxygen exist from the top to the bottom of biofilms and the bacterial cells located in nutrient poor areas have decreased metabolic activity and increased doubling times. These more or less dormant cells are therefore responsible for some of the tolerance to antibiotics. Biofilm growth is associated with an increased level of mutations. Bacteria in biofilms communicate by means of molecules, which activates certain genes responsible for production of virulence factors and, to some extent, biofilm structure. This phenomenon is called quorum sensing and depends upon the concentration of the quorum sensing molecules in a certain niche, which depends on the number of the bacteria. Biofilms can be prevented by antibiotic prophylaxis or early aggressive antibiotic therapy and they can be treated by chronic suppressive antibiotic therapy. Promising strategies may include the use of compounds which can dissolve the biofilm matrix and quorum sensing inhibitors, which increases biofilm susceptibility to antibiotics and phagocytosis.
Certolizumab Pegol for the Treatment of Crohn's Disease
Authors: William J. Sandborn, Brian G. Feagan, Simeon Stoinov, Pieter J. Honiball, Paul Rutgeerts, David Mason, Ralph Bloomfield, Stefan Schreiber
Journal: New England Journal of Medicine (2007)

In this article we provide a contemporary overview of available clinical data on certolizumab pegol, a pegylated anti-tumor necrosis factor (TNF) alpha agent that comprises a uniquely small protein, and its emerging role as a therapy for Crohn's disease (CD). The results from a comprehensive clinical trial program suggest that certolizumab pegol offers rapid and sustained remission of moderate to severe CD. Certolizumab pegol is an effective and well-tolerated therapy both in patients who have already received biologics and in patients who are anti-TNF naïve. Benefits of therapy include a stable dosing regimen, which allows for rapid induction of a clinical response followed by long-term maintenance of response and remission under one fixed dose. Treatment with certolizumab pegol has been shown to improve function and quality of life in patients with CD, and insights into the potential mechanisms by which certolizumab pegol effects a response in CD suggest that this agent may have the potential to slow or even modify disease progression. Early therapy is particularly effective and could help control CD progression and lessen the burden of disease on patients.
Impact of cigarette smoking on latent tuberculosis infection: does age matter?
Authors: Jia-Yih Feng, Shiang-Fen Huang, Wen-Ying Ting, Ming-Che Lee, Yu-Chun Chen, Yung-Yang Lin, Yu-Chin Lee, Wei-Juin Su
Journal: European Respiratory Journal (2013)

To the Editor: 

Latent tuberculosis infection (LTBI) is defined by evidence of immunological responses by Mycobacterium tuberculosis proteins in the absence of clinical symptoms/signs of active diseases [1]. People who have increased likelihood of tuberculosis (TB) exposure and those with clinical conditions that increased their risk of progressing from LTBI to TB disease are regarded as high-risk groups for developing TB disease and should be considered for LTBI testing and treatment. Both tuberculin skin test (TST) and T-cell based interferon-γ release assays (IGRAs) are available diagnostic tool for LTBI, but IGRAs avoid the interferences from bacille Calmette–Guerin (BCG) vaccination and non-tuberculous mycobacterium (NTM). Cigarette smoke has adverse effects in respiratory immune function and is widely reported to be associated with an increased risk of respiratory a tract infection, including TB [2, 3]. However, only a few studies investigated the impact of smoking on LTBI, and none of these studies used IGRAs to diagnose LTBI [4, 5].

The European Respiratory Journal recently published a perspective review focused on the role of diagnosis and treatment of LTBI to improve TB control and eventually TB elimination [6]. To eliminate TB on a global scale the identification and sterilisation of latently infected individuals, especially those in high-risk groups, is of paramount importance. Concerning the close correlation between cigarette smoking and active TB, the association between LTBI and smoking deserves further clarification with IGRAs as a diagnostic tool.

To elucidate the issue, we enrolled inpatients and outpatients who were considered at risk for LTBI and …
Jaundice following cardiopulmonary bypass
Authors: J. S. Robinson, F. R. Cole, P. Gibson, J. A. Simpson
Journal: Thorax (1967)

Serial liver function tests were performed in 29 adult patients following cardiopulmonary bypass for various open-heart procedures. In 22 patients there was a rise in serum bilirubin above 1·5 mg./100 ml., with clinical jaundice in 19 and bilirubinuria in 15 patients. The incidence of jaundice was related to age, the severity of pre-operative cardiac failure, and the duration of perfusion. Possible mechanisms for jaundice are discussed, and evidence is presented that liver damage may follow extracorporeal circulation.
The Meandering 45-Year Odyssey of a Clinical Immunologist
Authors: Thomas A. Waldmann
Journal: Annual Review of Immunology (2003)

My work on basic and clinical immunology has focused on the regulation of the human immune response and how its dysregulation can lead to immunodeficiency, autoimmune, and malignant disorders. The early focus in our laboratory was on pathogenic mechanisms underlying hypogammaglobulinemia. Our demonstration of active suppression by human suppressor T cells changed thinking about the pathogenesis of certain immunodeficiency disorders. Recently we have focused on the cytokines interleukin-2 (IL-2) and IL-15, which have competitive functions in adaptive immune responses. IL-2 is necessary to destroy self-reactive lymphocytes and thus favors peripheral tolerance to self-antigens, whereas IL-15 favors the persistence of lymphocytes involved in the memory and effector responses to invading pathogens but risks the development of inflammatory autoimmune diseases. Our murine anti-Tac monoclonal antibody exploits these differences, as does a humanized form (daclizumab) now approved for the prevention of renal allograft rejection. New forms of therapy directed at IL-2 and IL-15 receptors may be effective against certain neoplastic diseases and autoimmune disorders and in the prevention of allograft rejection.
Clinical Predictors for Fatal Pulmonary Embolism in 15 520 Patients With Venous Thromboembolism
Authors: Silvy Laporte, Patrick Mismetti, Hervé Décousus, Fernando Uresandi, Remedios Otero, Jose Luis Lobo, Manuel Monreal
Journal: Circulation (2008)

Clinical predictors for fatal pulmonary embolism (PE) in patients with venous thromboembolism have never been studied.Using data from the international prospective Registro Informatizado de la Enfermedad TromboEmbolica venosa (RIETE) registry about patients with objectively confirmed symptomatic acute venous thromboembolism, we determined independent predictive factors for fatal PE. Between March 2001 and July 2006, 15 520 consecutive patients (mean age+/-SD, 66.3+/-16.9 years; 49.7% men) with acute venous thromboembolism were included. Symptomatic deep-vein thrombosis without symptomatic PE was observed in 58.0% (n=9008) of patients, symptomatic nonmassive PE in 40.4% (n=6264), and symptomatic massive PE in 1.6% (n=248). At 3 months, the cumulative rates of overall mortality and fatal PE were 8.65% and 1.68%, respectively. On multivariable analysis, patients with symptomatic nonmassive PE at presentation exhibited a 5.42-fold higher risk of fatal PE compared with patients with deep-vein thrombosis without symptomatic PE (P<0.001). The risk of fatal PE was multiplied by 17.5 in patients presenting with a symptomatic massive PE. Other clinical factors independently associated with an increased risk of fatal PE were immobilization for neurological disease, age >75 years, and cancer.PE remains a potentially fatal disease. The clinical predictors identified in the present study should be included in any clinical risk stratification scheme to optimally adapt the treatment of PE to the risk of the fatal outcome.
P2 Purinoceptor Saturation by Adenosine Triphosphate Impairs Renal Autoregulation in Dogs
Authors: DEWAN S. A. MAJID, EDWARD W. INSCHO, L. GABRIEL NAVAR
Journal: Journal of the American Society of Nephrology (1999)

Abstract. Recent studies have suggested a role for P2 purinoceptors on vascular smooth muscle cells in the mechanism of renal autoregulation. Experiments were performed in anesthetized dogs ( n = 9) to examine renal blood flow (RBF) auto-regulatory efficiency before and after saturation of P2 purinoceptors with acute intra-arterial administration of ATP (1 mg/kg per min). Dogs were pretreated with the nitric oxide synthase inhibitor nitro-L-arginine (NLA) (50 μg/kg per min), to avoid endothelial P2 receptor-mediated effects on nitric oxide release caused by the intra-arterial ATP infusions. NLA treatment decreased RBF (5.3 ± 0.3 to 3.6 ± 0.2 ml/min per g) and sodium excretion (3.6 ± 0.4 to 0.9 ± 0.2 ml/min per g) without producing significant changes in GFR (0.92 ± 0.04 to 0.90 ± 0.06 ml/min per g) or RBF autoregulatory efficiency. ATP administration to NLA-treated dogs resulted in further decreases in RBF (2.8 ± 0.2 ml/min per g), GFR (0.58 ± 0.05 ml/min per g), and sodium excretion (0.6 ± 0.2 μmol/min per g). In addition, there was marked impairment of RBF autoregulatory efficiency during ATP infusion. The slopes of the arterial pressure-blood flow relationships at renal arterial pressures of &gt;75 mmHg were significantly altered, from 0.003 ± 0.001 to 0.2 ± 0.002 ml/min per g per mmHg. Discontinuation of ATP infusion restored RBF autoregulatory efficiency. Norepinephrine (5 μg/kg per min) administration in these NLA-treated dogs decreased RBF (2.5 ± 0.3 ml/min per g; n = 4) to a similar extent, compared with ATP, but did not impair RBF autoregulation. These results support the hypothesis that P2 purinoceptors may be involved in mediating autoregulatory adjustments in renal vascular resistance.
Acute Effects of Continuous Positive Airway Pressure on Cardiac Sympathetic Tone in Congestive Heart Failure
Authors: David M. Kaye, Darren Mansfield, Ann Aggarwal, Matthew T. Naughton, Murray D. Esler
Journal: Circulation (2001)

Depressed ventricular performance and neurohormonal activation are key pathophysiological features of congestive heart failure (CHF). Although angiotensin-converting enzyme inhibitors and beta-adrenoceptor blockers exert beneficial effects in CHF, mortality remains unacceptably high, and the development of further therapeutic approaches is warranted. Recent data suggest that continuous positive airway pressure (CPAP) may be of benefit in the treatment of CHF, although the mechanism for this action is incompletely understood.In the present study, we examined the effect of short-term CPAP (10 cm H(2)O for 10 minutes) on hemodynamics (Swan Ganz catheter) and total systemic and cardiac sympathetic activity (norepinephrine spillover method) in 14 CHF patients in New York Heart Association class III. The application of CPAP was associated with a fall in cardiac output (4.8+/-0.3 to 4.4+/-0.2 L/min; P<0.05) and a significant reduction in cardiac norepinephrine spillover (370+/-58 to 299+/-55 pmol/min; P<0.05), although total systemic norepinephrine spillover was unchanged.The short-term application of CPAP results in an inhibition of cardiac sympathetic nervous activity. Further investigation into the potential value of long-term CPAP in CHF patients is warranted.
Increased Activity of Endogenous Endothelin in Patients With Type II Diabetes Mellitus
Authors: Carmine Cardillo, Umberto Campia, Melissa B. Bryant, Julio A. Panza
Journal: Circulation (2002)

Endothelial dysfunction may contribute to the risk of premature atherosclerosis in patients with diabetes. Endothelin (ET-1) may be involved in this process by activating smooth muscle cell mitogenesis and leukocyte adhesion. We sought to assess the activity of endogenous ET-1 in a group of patients with type II diabetes mellitus with the use of antagonists of ET-1 receptors.Forearm blood flow (FBF) responses (strain gauge plethysmography) to intraarterial infusion of a selective blocker of ET(A) receptors (BQ-123) and, on a different occasion, to ET-1, were measured in 15 patients with diabetes and 12 healthy controls. In addition, 5 patients with diabetes received coinfusion of BQ-123 and BQ-788 (a selective blocker of ET(B) receptors). In normal subjects, BQ-123 did not significantly modify FBF from baseline (P=0.16). In contrast, BQ-123 administration resulted in a significant vasodilator response in patients with diabetes (P<0.001). Infusion of exogenous ET-1 resulted in lower vasoconstrictor responses in patients with diabetes than in controls (P=0.001), whereas the vasoconstrictor response to norepinephrine was similar in the 2 groups (P=0.78). In patients with diabetes, the vasodilator response to selective ET(A) blockade was not significantly modified by nonselective blockade of ET-1 receptors obtained by coinfusion of BQ-123 and BQ-788.The activity of endogenous ET-1 on ET(A) receptors is enhanced in the resistance vessels of patients with diabetes, whereas their sensitivity to exogenous ET-1 is blunted. This abnormality may participate in the pathophysiology of vascular complications associated with diabetes.
Failure of Empirical Systemic Antifungal Therapy in Mechanically Ventilated Critically Ill Patients
Authors: Sébastien Bailly, Lila Bouadma, Elie Azoulay, Maité Garrouste Orgeas, Christophe Adrie, Bertrand Souweine, Carole Schwebel, Danièle Maubon, Rebecca Hamidfar-Roy, Michael Darmon, Michel Wolff, Muriel Cornet, Jean-François Timsit
Journal: American Journal of Respiratory and Critical Care Medicine (2015)

Systemic antifungal treatments are empirically administered to the sickest critically ill patients, often without documented invasive fungal infection.To estimate the impact of systemic antifungal treatment on 30-day survival of patients suspected to have invasive candidiasis.All nonneutropenic, nontransplant recipients managed in five intensive care units intubated for at least 5 days, and free of invasive candidiasis, were included. To account for differences in patients' characteristics recorded daily before study end point, a causal model for longitudinal data was used to assess benefits from antifungal treatment. The composite primary end point was hospital mortality or occurrence of invasive candidiasis.Among 1,491 patients, 100 (6.7%) received antifungal treatment for a suspected infection. Patients treated with antifungals were more severely ill than untreated patients. Within the 30-day follow-up period, 363 (24.3%) patients died, and 22 (1.5%) exhibited documented invasive candidiasis. After adjustment on baseline and time-dependent confounders (underlying illness, severity, invasive procedures, Candida colonization), and using a marginal structural model for longitudinal data, treatment was not associated with a decreased risk of mortality or of occurrence of invasive candidiasis (hazard ratio, 1.05; 95% confidence interval, 0.56-1.96; P = 0.91).This study failed to show outcome benefits for empirical systemic antifungal therapy in the sickest critically ill, nonneutropenic, nontransplanted patients. The post hoc power did not allow us to conclude to an absence of treatment effect especially for specific subgroups. Studies to refine indications for empirical treatment based on surrogate markers of invasive candidiasis are warranted.