tbuckley/cabot-search huggingface dataset:
Use of Positron Emission Tomography in Pharmacokinetic Studies to Investigate Therapeutic Advantage in a Phase I Study of 120-Hour Intravenous Infusion XR5000
Authors: D.J. Propper, J. de Bono, A. Saleem, S. Ellard, E. Flanagan, J. Paul, T.S. Ganesan, D.C. Talbot, E.O. Aboagye, P. Price, A.L. Harris, C. Twelves
Journal: Journal of Clinical Oncology (2003)

Purpose: XR5000 (N-[2-(dimethylamino)ethyl]acridine-4-carboxamide) is a topoisomerase I and II inhibitor. Because the cytotoxicity of XR5000 increases markedly with prolonged exposure, we performed a phase I study of weekly XR5000 by 120-hour continuous infusion over 3 weeks. Patients and Methods: Twenty-four patients with advanced solid cancer were treated at seven dose levels (700 to 4,060 mg/m 2 /120 hrs) for a total of 67 cycles. Three patients underwent positron emission tomography (PET) studies at the maximum-tolerated dose (MTD) to evaluate normal tissue and tumor carbon-11 radiolabeled XR5000 ([ 11 C]XR5000) pharmacokinetics. Results: The dose-limiting toxicity was National Cancer Institute Common Toxicity Criteria (version 1) grade 4 chest and abdominal pain affecting the single patient receiving 4,060 mg/m 2 /120 hours, and the MTD was 3,010 mg/m 2 /120 hours. Other grade 3–4 toxicities, affecting single patients at the MTD, were myelosuppression (grade 4), raised bilirubin, vomiting, and somnolence (all grade 3). There was one partial response (adenocarcinoma of unknown primary); the remainder had progressive disease. [ 11 C]XR5000 distributed well into the three tumors studied by PET. Tumor uptake (maximum concentration or area under the concentration versus time curve [AUC]) was less than in normal tissue in which the tumors were located. Tumor exposure (AUC; mean ± SD in m 2 /mL/sec) increased when [ 11 C]XR5000 was administered during an infusion of XR5000 (0.403 ± 0.1), compared with [ 11 C]XR5000 given alone (0.292 ± 0.1; P &lt; .05), indicating that tumor drug exposure was not saturated. Conclusion: The recommended dose for XR5000 in phase II studies is 3,010 mg/m 2 /120 hours. PET studies with 11 C-labeled drug were feasible and demonstrated in vivo distribution into tumors. Saturation of tumor exposure was not reached at the MTD.
The effect of disease duration and disease activity on the risk of cardiovascular disease in rheumatoid arthritis patients
Authors: Elke E A Arts, Jaap Fransen, Alfons A den Broeder, Calin D Popa, Piet L C M van Riel
Journal: Annals of the Rheumatic Diseases (2014)

Disease duration and disease activity may be associated with an increased risk of cardiovascular disease (CVD) in rheumatoid arthritis (RA). The objectives of this study were to investigate (1) the relationship between duration of inflammation and the development of CVD in RA patients and (2) the relationship between RA disease activity over time and CVD in patients with RA.RA patients with a follow-up of ≥6 months in the Nijmegen early RA cohort without prior CVD were included. Disease activity over time was calculated using the time-averaged 28 joint disease activity score (DAS28) for each patient. Kaplan-Meier survival analysis and Cox proportional hazards regression were used for the analyses.During follow-up of the 855 patients that were included, 154 CV events occurred. The course of hazards over time did not indicate a change in the risk of CVD over the course of RA (disease duration), which is also reflected by the absence of a deflection in the survival curves. The survival distributions did not differ between patients with a disease duration of <10 years or >10 years (Log-rank test: p=0.82). Time-averaged DAS28 was significantly associated with CVD (p=0.002) after correction for confounders.Disease duration does not appear to independently affect the risk of CVD. The risk of CVD in RA patients was not increased after 10 years of disease duration compared with the first 10 years. Disease activity over time may contribute to the risk of CVD.
Outcomes of PCI at Hospitals with or without On-Site Cardiac Surgery
Authors: Thomas Aversano, Cynthia C. Lemmon, Li Liu
Journal: New England Journal of Medicine (2012)

Performance of percutaneous coronary intervention (PCI) is usually restricted to hospitals with cardiac surgery on site. We conducted a noninferiority trial to compare the outcomes of PCI performed at hospitals without and those with on-site cardiac surgery.We randomly assigned participants to undergo PCI at a hospital with or without on-site cardiac surgery. Patients requiring primary PCI were excluded. The trial had two primary end points: 6-week mortality and 9-month incidence of major adverse cardiac events (the composite of death, Q-wave myocardial infarction, or target-vessel revascularization). Noninferiority margins for the risk difference were 0.4 percentage points for mortality at 6 weeks and 1.8 percentage points for major adverse cardiac events at 9 months.A total of 18,867 patients were randomly assigned in a 3:1 ratio to undergo PCI at a hospital without on-site cardiac surgery (14,149 patients) or with on-site cardiac surgery (4718 patients). The 6-week mortality rate was 0.9% at hospitals without on-site surgery versus 1.0% at those with on-site surgery (difference, -0.04 percentage points; 95% confidence interval [CI], -0.31 to 0.23; P=0.004 for noninferiority). The 9-month rates of major adverse cardiac events were 12.1% and 11.2% at hospitals without and those with on-site surgery, respectively (difference, 0.92 percentage points; 95% CI, 0.04 to 1.80; P=0.05 for noninferiority). The rate of target-vessel revascularization was higher in hospitals without on-site surgery (6.5% vs. 5.4%, P=0.01).We found that PCI performed at hospitals without on-site cardiac surgery was noninferior to PCI performed at hospitals with on-site cardiac surgery with respect to mortality at 6 weeks and major adverse cardiac events at 9 months. (Funded by the Cardiovascular Patient Outcomes Research Team [C-PORT] participating sites; ClinicalTrials.gov number, NCT00549796.).
Artificial Neural Networks Analysis of Surface-Enhanced Laser Desorption/Ionization Mass Spectra of Serum Protein Pattern Distinguishes Colorectal Cancer from Healthy Population
Authors: Yi-ding Chen, Shu Zheng, Jie-kai Yu, Xun Hu
Journal: Clinical Cancer Research (2004)

Abstract Purpose: The low specificity and sensitivity of the carcinoembryonic antigen test makes it not an ideal biomarker for the detection of colorectal cancer. We developed and evaluated a proteomic approach for the simultaneous detection and analysis of multiple proteins for distinguishing individuals with colorectal cancer from healthy individuals. Experimental Design: We subjected serum samples (including 55 colorectal cancer patients and 92 age- and sex-matched healthy individuals) from 147 individuals, for analysis by surface-enhanced laser desorption/ionization (SELDI) mass spectrometry. Peaks were detected with Ciphergen SELDI software version 3.0. Using a multilayer artificial neural network with a back propagation algorithm, we developed a classifier for separating the colorectal cancer groups from the healthy groups. Results: The artificial neural network classifier separated the colorectal cancer from the healthy samples, with a sensitivity of 91% and specificity of 93%. Four top-scored peaks, at m/z of 5,911, 8,930, 8,817, and 4,476, were finally selected as the potential “fingerprints” for detection of colorectal cancer. Conclusions: The combination of SELDI-TOF mass spectrometry with the artificial neural networks in the analysis of serum protein yields significantly higher sensitivity and specificity values for the detection and diagnosis of colorectal cancer.
FMF50: a score for assessing outcome in familial Mediterranean fever
Authors: Seza Ozen, Erkan Demirkaya, Ali Duzova, Ozlem Erdogan, Eren Erken, Ahmet Gul, Ozgur Kasapcopur, Timucin Kasifoglu, Bunyamin Kisacik, Huri Ozdogan, Mehmet Tunca, Cengizhan Acikel
Journal: Annals of the Rheumatic Diseases (2014)

Colchicine is the main treatment for familial Mediterranean fever (FMF). However, biological agents and other treatments are available for patients who are unable to receive optimal treatment.To develop outcome criteria that define response to treatment.Two rounds of Delphi exercise were followed by a consensus conference enabling the definition of the criteria to be employed. Data for patients with FMF responding and resistant to their treatment were obtained from the FMF Arthritis Vasculitis and Orphan disease Research in paediatric rheumatology (FAVOR) website. The suggested criteria were analysed and validated in this patient cohort. Sensitivity/specificity measures and the ability of the score to discriminate between patients with active and inactive disease via the best cut-off score were calculated by a receiver operating characteristic analysis.Compliance with the maximum dose of the drug was considered essential for evaluation of the patients. Seven criteria were suggested in the consensus conference. The performance of each criterion, in differentiating between resistant and responsive patients, was tested. The final set of criteria was defined as at least 50% improvement in five of six criteria, without worsening in any one defined response to treatment with a very high sensitivity and specificity. The items of this FMF50 included: 1. Percentage change in the frequency of attacks with the treatment. 2. Percentage change in the duration of attacks with the treatment. 3. Patients/parents' global assessment of disease severity (10 cm visual analogue scale (VAS)). 4. Physicians' global assessment of disease severity (10 cm VAS). 5. Percentage change in arthritis attacks with the treatment. 6. Percentage change in C-reactive protein, erythrocyte sedimentation rate or serum amyloid A level with the treatment.The FMF50 produced is a user-friendly measurement tool to guide physicians and can be used in clinical trials.
Impact of Genetic Diagnosis on Clinical Management of Patients With Congenital Heart Disease
Authors: Martina Brueckner
Journal: Circulation (2012)

shunt surgery in 1945 changed major congenital heart disease (CHD) from a universally lethal condition into a survivable one. 1 In the 50 years that followed, rapid progress in anatomic diagnosis via echocardiography and dramatic improvement in surgical and catheterization techniques resulted in survival to adulthood and greatly improved quality of life for many individuals with CHD.Despite this, continuing progress in caring for individuals with the most complex forms of CHD has become incremental.One of the particularly frustrating aspects of managing patients with very complex CHD is that the outcomes are highly variable, even when accounting for surgical skill and anatomic complexity.In this issue of Circulation, Nakhleh et al 2 show that a subset of patients with CHD and heterotaxy have airway ciliary dysfunction that may account for increased morbidity and mortality independently of the complexity of the CHD.This finding highlights a critical point that will surely affect patient care in the years to come; improving our understanding of the genetic origin of CHD is likely to affect response to therapy.The hope is that individualized therapy for CHD based on the underlying genetics will contribute to the next major improvement in outcome.
Development of an Autocrine Neuregulin Signaling Loop with Malignant Transformation of Human Breast Epithelial Cells
Authors: Qunfang Li, Sharlin Ahmed, Jeffrey A. Loeb
Journal: Cancer Research (2004)

Abstract Neuregulin (NRG) is a heparin-binding factor that activates members of the epidermal growth factor family of tyrosine kinase receptors including erbB2 that is overexpressed in more aggressive types of breast cancer. The exact role that NRG plays in breast cancer is complicated by the fact that NRG has been shown to have both proliferative and antiproliferative effects, depending on the breast cancer cell line used. Using an isogenic series of breast epithelial cell lines (MCF10A) ranging from benign to malignant, we found that the actions of NRG changed from antiproliferative to proliferative as the cells progress to cancer. This correlated with a progressive inability of NRG to down-regulate a group of proliferation genes identified previously using cDNA microarrays. As the cells progress to malignancy, they expressed higher levels of erbB2 and lower levels of erbB3 and secreted high levels of NRG into the culture media, resulting in high basal levels of erbB receptor phosphorylation. Disruption of this autocrine signaling loop by blocking ligand-induced receptor activation inhibited cancer cell proliferation. These results demonstrate that the transition of MCF10A cells from normal to premalignant to malignant correlates with the development of a constitutively active autocrine NRG signaling loop that promotes cell proliferation and suggest that disrupting this autocrine loop may provide an important therapeutic measure to control breast cancer cell growth.
In search of the tendon holy grail: predictable clinical outcomes
Authors: Jill Cook
Journal: British Journal of Sports Medicine (2009)

In search of the tendon holy grail: predictable clinical outcomes Jill CookWhat is your first reaction when you find out your next patient has a long-term tendinopathy?I suspect you want to hide or get an urgent phone call that drags you away from the practice.You know that the person will have tried multiple interventions, probably had several injections, read all the literature about treatments for tendinopathy on the internet and want an immediate and lifelong cure.You also know that your assessment will take well into your next patient's time allotment and even then it will remain difficult to prioritise treatments and to explain the rationale behind your plan to the patient.Even as a tendon researcher and part-time clinician whose practice consists solely of tendinopathy patients, my reactions to chronic tendinopathy patients are similar.
A functional granulocyte colony-stimulating factor receptor is required for normal chemoattractant-induced neutrophil activation
Authors: Tomoko Betsuyaku, Fulu Liu, Robert M. Senior, Jeffery S. Haug, Eric J. Brown, Samuel L. Jones, Kouji Matsushima, Daniel C. Link
Journal: Journal of Clinical Investigation (1999)

Granulocyte colony-stimulating factor (G-CSF) is a hematopoietic growth factor that is widely used to treat neutropenia. In addition to stimulating polymorphonuclear neutrophil (PMN) production, G-CSF may have significant effects on PMN function. Because G-CSF receptor (G-CSFR)–deficient mice do not have the expected neutrophilia after administration of human interleukin-8 (IL-8), we examined the effect of the loss of G-CSFR on IL-8–stimulated PMN function. Compared with wild-type PMNs, PMNs isolated from G-CSFR–deficient mice demonstrated markedly decreased chemotaxis to IL-8. PMN emigration into the skin of G-CSFR–deficient mice in response to IL-8 was also impaired. Significant chemotaxis defects were also seen in response to N-formyl-methionyl-leucyl-phenylalanine, zymosan-activated serum, or macrophage inflammatory protein-2. The defective chemotactic response to IL-8 does not appear to be due to impaired chemoattractant receptor function, as the number of IL-8 receptors and chemoattractant-induced calcium influx, actin polymerization, and release of gelatinase B were comparable to those of wild-type PMNs. Chemoattractant-induced adhesion of G-CSFR–deficient PMNs was significantly impaired, suggesting a defect in β2-integrin activation. Collectively, these data demonstrate that selective defects in PMN activation are present in G-CSFR–deficient mice and indicate that G-CSF plays an important role in regulating PMN chemokine responsiveness.
Primary sternal osteomyelitis.
Authors: C A Kelly, M N Chetty
Journal: Thorax (1985)

Primary osteomyelitis of' the sternum is a rare condition.Infection may follow chest trauma and is a recognised complication of open heart surgery, with a reported incidence of 1-2%.' Since the detailed review by Wilensky and Samuels in 19262 there have' been only occasional reports.We describe a case of chronic sternal infection without preceding trauma and present a review of published reports.Case report
alpha-fetoprotein in noneoplastic hepatic disorders
Authors: J. R. Bloomer
Journal: JAMA (1975)

Serum alpha-fetoprotein levels were measured by radioimmunoassay in 473 patients with biopsy-proved noneoplastic hepatic disorders; 22% had values greater than 40 ng/ml, whereas only 1 of 350 patients with nonhepatic benign diseases had a value greater than this. Levels exceeded 40 ng/ml in more than 30% of patients with various types of hepatitis, and in 0% to 15% with inactive postnecrotic cirrhosis, primary biliary cirrhosis, biliary tract obstruction, and alcoholic liver disease. Values greater than 500 mg/ml were observed solely in viral subacute hepatic necrois. Only one patient had a level exceeding 3,000 ng/ml, the concentration at which alpha-fetoprotein is detectable by agar-gel diffusion. Of 75 patients with hepatoma, serum alpha-fetoprotein levels exceeded 40 ng/ml in 69%, and exceeded 3,000 ng/ml in 48%. These studies indicate that serum alpha-fetoprotein levels are elevated in several nonneoplastic hepatic disorders when a sensitive assay is used; this phenomenon may reflect hepatic regeneration.
Periorbital pigmented and reticulated junctional melanocytic naevus: a report of two cases
Authors: J.X. Sousa, E.D. Omar, I.M. Bernardelli, M.N. Sotto, C.G. Santi, R. Romiti, M.C.R. Machado
Journal: British Journal of Dermatology (2006)

Journal Article Periorbital pigmented and reticulated junctional melanocytic naevus: a report of two cases Get access J.X. Sousa, Jr, J.X. Sousa, Jr Department of Dermatology, Hospital das Clinicas Sao Paolo, Sao Paolo, Brazil E‐mail: jxsj@yahoo.com Search for other works by this author on: Oxford Academic Google Scholar E.D. Omar, E.D. Omar Department of Dermatology, Hospital das Clinicas Sao Paolo, Sao Paolo, Brazil E‐mail: jxsj@yahoo.com Search for other works by this author on: Oxford Academic Google Scholar I.M. Bernardelli, I.M. Bernardelli Department of Dermatology, Hospital das Clinicas Sao Paolo, Sao Paolo, Brazil E‐mail: jxsj@yahoo.com Search for other works by this author on: Oxford Academic Google Scholar M.N. Sotto, M.N. Sotto Department of Dermatology, Hospital das Clinicas Sao Paolo, Sao Paolo, Brazil E‐mail: jxsj@yahoo.com Search for other works by this author on: Oxford Academic Google Scholar C.G. Santi, C.G. Santi Department of Dermatology, Hospital das Clinicas Sao Paolo, Sao Paolo, Brazil E‐mail: jxsj@yahoo.com Search for other works by this author on: Oxford Academic Google Scholar R. Romiti, R. Romiti Department of Dermatology, Hospital das Clinicas Sao Paolo, Sao Paolo, Brazil E‐mail: jxsj@yahoo.com Search for other works by this author on: Oxford Academic Google Scholar M.C.R. Machado M.C.R. Machado Department of Dermatology, Hospital das Clinicas Sao Paolo, Sao Paolo, Brazil E‐mail: jxsj@yahoo.com Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 156, Issue 2, 1 February 2007, Pages 383–384, https://doi.org/10.1111/j.1365-2133.2006.07624.x Published: 01 February 2007
Influence Function for Robust Phylogenetic Reconstructions
Authors: A. Bar-Hen, M. Mariadassou, M.-A. Poursat, P. Vandenkoornhuyse
Journal: Molecular Biology and Evolution (2008)

Based on the computation of the influence function, a tool to measure the impact of each piece of sampled data on the statistical inference of a parameter, we propose to analyze the support of the maximum-likelihood (ML) tree for each site. We provide a new tool for filtering data sets (nucleotides, amino acids, and others) in the context of ML phylogenetic reconstructions. Because different sites support different phylogenic topologies in different ways, outlier sites, that is, sites with a very negative influence value, are important: they can drastically change the topology resulting from the statistical inference. Therefore, these outlier sites must be clearly identified and their effects accounted for before drawing biological conclusions from the inferred tree. A matrix containing 158 fungal terminals all belonging to Chytridiomycota, Zygomycota, and Glomeromycota is analyzed. We show that removing the strongest outlier from the analysis strikingly modifies the ML topology, with a loss of as many as 20% of the internal nodes. As a result, estimating the topology on the filtered data set results in a topology with enhanced bootstrap support. From this analysis, the polyphyletic status of the fungal phyla Chytridiomycota and Zygomycota is reinforced, suggesting the necessity of revisiting the systematics of these fungal groups. We show the ability of influence function to produce new evolution hypotheses.
Myogenic and Neurogenic Factors in the Control of Pyeloureteral Motility and Ureteral Peristalsis
Authors: Paolo Santicioli, Carlo Alberto Maggi
Journal: Pharmacological Reviews (1998)

The main, and possibly only, function of the pyeloureteral complex is to ensure the unidirectional transport of urine from the kidney to the urinary bladder. An extremely efficient set of mechanisms operates to achieve this target: the basic process regulating ureteral peristalsis is myogenic, being