tbuckley/cabot-search huggingface dataset:
Predictors of Vinorelbine Pharmacokinetics and Pharmacodynamics in Patients With Cancer
Authors: Mark Wong, Rosemary L. Balleine, Elaine Y.L. Blair, Andrew J. McLachlan, Stephen P. Ackland, Madhu B. Garg, Scott Evans, David Farlow, Michael Collins, Laurent P. Rivory, Janelle M. Hoskins, Graham J. Mann, Christine L. Clarke, Howard Gurney
Journal: Journal of Clinical Oncology (2006)

Purpose Marked interindividual variation in drug disposition and toxicity pose an ongoing challenge to chemotherapy dosage individualization. The aim of this study was to evaluate pretreatment clinical features, genotype and functional indicators of drug clearance as predictors of vinorelbine clearance, and myelotoxicity that could inform dosage optimization. Patients and Methods Forty-one patients with cancer received a 60 mg intravenous dose of vinorelbine. Pretreatment routine body size measurements and blood tests were performed. Midazolam clearance and hepatic technetium labeled sestamibi ( 99m Tc-MIBI) clearance were used to investigate CYP3A and ABCB1 (MDR1, P-glycoprotein) phenotype respectively and selected single nucleotide polymorphisms in CYP3A and ABCB1 were documented. A limited blood sampling strategy was employed and vinorelbine concentrations were determined by high-performance liquid chromatography. Posterior Bayesian estimates of vinorelbine clearance were obtained for each patient using population pharmacokinetic modeling. Myelotoxicity was estimated from the fractional survival of neutrophils post-treatment. Results There was 4.3-fold variation in vinorelbine clearance across the cohort. In a multivariable analysis, pretreatment estimated creatinine clearance (P &lt; .01) and hepatic 99m Tc-MIBI clearance (P = .01) were independent predictors of vinorelbine clearance. Fractional survival of neutrophils ranged from 1.3% to 100% and was significantly correlated with vinorelbine clearance (P &lt; .01). Body-surface area was the only pretreatment predictor of fractional survival of neutrophils independent of vinorelbine clearance (P = .02). Conclusion Specific indicators of drug clearance provide predictive information about vinorelbine pharmacokinetics, and body-surface area, probably reflecting normal bone marrow reserve, provides an additional pharmacodynamic indicator. Use of a fixed dose of vinorelbine with modifications guided by pretreatment measures is worthy of prospective evaluation.
Non-invasive ventilation
Authors: A Anton
Journal: Thorax (2002)

<h3>Abstract</h3> Encapsulated ferritins belong to the universally distributed ferritin superfamily, which function as iron detoxification and storage systems. Encapsulated ferritins have a distinct annular structure and must associate with an encapsulin nanocage to form a competent iron store that is capable of holding significantly more iron than classical ferritins. The catalytic mechanism of iron oxidation in the ferritin family is still an open question, due to differences in organization of the ferroxidase catalytic site and secondary metal binding sites vicinal to this. We have previously identified a metal binding site on the inner surface of the <i>Rhodospirillum rubrum</i> encapsulated ferritin at the interface between the two-helix subunits and proximal to the ferroxidase center. Here we present a comprehensive structural and functional study to investigate the functional relevance of this proposed iron entry site by means of enzymatic assays, mass-spectrometry, and X-ray crystallography. We show that catalysis occurs in the ferroxidase center and suggest a dual role for the secondary site, which both serves to attract metal ions to the ferroxidase center and acts as a flow-restricting valve to limit the activity of the ferroxidase center. Moreover, confinement of encapsulated ferritins within the encapsulin nanocage, while enhancing the ability of the encapsulated ferritin to undergo catalysis, does not influence the function of the secondary site.
Bone Marrow Mesenchymal Stem Cells Stimulate Cardiac Stem Cell Proliferation and Differentiation
Authors: Konstantinos E. Hatzistergos, Henry Quevedo, Behzad N. Oskouei, Qinghua Hu, Gary S. Feigenbaum, Irene S. Margitich, Ramesh Mazhari, Andrew J. Boyle, Juan P. Zambrano, Jose E. Rodriguez, Raul Dulce, Pradip M. Pattany, David Valdes, Concepcion Revilla, Alan W. Heldman, Ian McNiece, Joshua M. Hare
Journal: Circulation Research (2010)

Rationale: The regenerative potential of the heart is insufficient to fully restore functioning myocardium after injury, motivating the quest for a cell-based replacement strategy. Bone marrow–derived mesenchymal stem cells (MSCs) have the capacity for cardiac repair that appears to exceed their capacity for differentiation into cardiac myocytes. Objective: Here, we test the hypothesis that bone marrow derived MSCs stimulate the proliferation and differentiation of endogenous cardiac stem cells (CSCs) as part of their regenerative repertoire. Methods And Results: Female Yorkshire pigs (n=31) underwent experimental myocardial infarction (MI), and 3 days later, received transendocardial injections of allogeneic male bone marrow–derived MSCs, MSC concentrated conditioned medium (CCM), or placebo (Plasmalyte). A no-injection control group was also studied. MSCs engrafted and differentiated into cardiomyocytes and vascular structures. In addition, endogenous c-kit + CSCs increased 20-fold in MSC-treated animals versus controls ( P &lt;0.001), there was a 6-fold increase in GATA-4 + CSCs in MSC versus control ( P &lt;0.001), and mitotic myocytes increased 4-fold ( P =0.005). Porcine endomyocardial biopsies were harvested and plated as organotypic cultures in the presence or absence of MSC feeder layers. In vitro, MSCs stimulated c-kit + CSCs proliferation into enriched populations of adult cardioblasts that expressed Nkx2–5 and troponin I. Conclusions: MSCs stimulate host CSCs, a new mechanism of action underlying successful cell-based therapeutics.
Glucuronidation and its Role in Regulation of Biological Activity of Drugs
Authors: G J Mulder
Journal: The Annual Review of Pharmacology and Toxicology (1992)

Heme oxygenases (HO) catabolize free heme, that is, iron (Fe) protoporphyrin (IX), into equimolar amounts of Fe2+, carbon monoxide (CO), and biliverdin. The stress-responsive HO-1 isoenzyme affords protection against programmed cell death. The mechanism ...Read More
Prognostic Significance of <b> <i>TP53</i> </b> Tumor Suppressor Gene Expression and Mutations in Human Osteosarcoma
Authors: Emilios E. Pakos, Panayiotis A. Kyzas, John P. A. Ioannidis
Journal: Clinical Cancer Research (2004)

Abstract Purpose: Various studies examining the relationship between tumor suppressor protein TP53 overexpression and/or TP53 gene mutations and the response to chemotherapy and clinical outcome in patients with osteosarcoma have yielded inconclusive results. The purpose of the current study was to evaluate the relation of TP53 status with response to chemotherapy and/or clinical outcome in osteosarcoma. Experimental Design: We conducted a meta-analysis of 16 studies (n = 499 patients) that evaluated the correlation between TP53 status and histologic response to chemotherapy and 2-year survival. Data were synthesized in summary receiver operating characteristic curves and with summary likelihood ratios (LRs) and risk ratios. Results: The quantitative synthesis showed that TP53 status is not a prognostic factor for the response to chemotherapy. The positive LR was 1.21 (95% confidence interval, 0.86–1.71), and the negative LR was 0.91 (95% confidence interval, 0.77–1.07). There was no significant between-study heterogeneity. TP53-positive status tended to be associated with a worse 2-year survival, but the overall results were not formally statistically significant. The association was formally significant in studies that clearly stated that measurements were blinded to outcomes (risk ratio, 2.05; 95% confidence interval, 1.23–3.44), and in studies using reverse transcription-PCR for evaluating TP53 alterations (risk ratio, 1.76; 95% confidence interval, 1.07–2.91). Conclusions: TP53 status is not associated with the histologic response to chemotherapy in patients with osteosarcoma, whereas TP53 gene alterations may be associated with decreased survival.
Study of self-reported hypersensitivity to electromagnetic fields in California.
Authors: Patrick Levallois, Raymond Neutra, Geraldine Lee, Lilia Hristova
Journal: Environmental Health Perspectives (2002)

Cases of alleged hypersensitivity to electromagnetic fields (EMFs) have been reported for more than 20 years, and some authors have suggested some connection with the "multiple chemical sensitivity" illness. We report the results of a telephone survey among a sample of 2,072 Californians. Being "allergic or very sensitive" to being near electrical devices was reported by 68 subjects, resulting in an adjusted prevalence of 3.2% (95% confidence interval = 2.8, 3.7). Twenty-seven subjects (1.3%) reported sensitivity to electrical devices but no sensitivity to chemicals. Characteristics of the people reporting hypersensitivity to EMFs were generally different from those of people reporting being allergic to everyday chemicals. Alleging environmental illness or multiple chemical sensitivity diagnosed by a doctor was the strongest predictor of reporting being hypersensitive to EMFs in this population. Other predictive factors apart from self-reporting chemical sensitivity were race/ethnicity other than White, Black, or Hispanic; having low income; and being unable to work. The perception of risk of exposure to EMFs through the use of hair dryers (vs. exposure to power and distribution lines) was the factor the most associated with self-reporting about hypersensitivity to EMFs. However, risk perception was not sufficient to explain the characteristics of people reporting this disorder.
Trapping Cardiac Recessive Mutants via Expression-Based Insertional Mutagenesis Screening
Authors: Yonghe Ding, Weibin Liu, Yun Deng, Beninio Jomok, Jingchun Yang, Wei Huang, Karl J. Clark, Tao P. Zhong, Xueying Lin, Stephen C. Ekker, Xiaolei Xu
Journal: Circulation Research (2013)

Mutagenesis screening is a powerful genetic tool for probing biological mechanisms underlying vertebrate development and human diseases. However, the increased colony management efforts in vertebrates impose a significant challenge for identifying genes affecting a particular organ, such as the heart, especially those exhibiting adult phenotypes on depletion.We aim to develop a facile approach that streamlines colony management efforts via enriching cardiac mutants, which enables us to screen for adult phenotypes.The transparency of the zebrafish embryos enabled us to score 67 stable transgenic lines generated from an insertional mutagenesis screen using a transposon-based protein trapping vector. Fifteen lines with cardiac monomeric red fluorescent protein reporter expression were identified. We defined the molecular nature for 10 lines and bred them to homozygosity, which led to the identification of 1 embryonic lethal, 1 larval lethal, and 1 adult recessive mutant exhibiting cardiac hypertrophy at 1 year of age. Further characterization of these mutants uncovered an essential function of methionine adenosyltransferase II, α a (mat2aa) in cardiogenesis, an essential function of mitochondrial ribosomal protein S18B (mrps18b) in cardiac mitochondrial homeostasis, as well as a function of DnaJ (Hsp40) homolog, subfamily B, member 6b (dnajb6b) in adult cardiac hypertrophy.We demonstrate that transposon-based gene trapping is an efficient approach for identifying both embryonic and adult recessive mutants with cardiac expression. The generation of a zebrafish insertional cardiac mutant collection shall facilitate the annotation of a vertebrate cardiac genome, as well as enable heart-based adult screens.
Mood Stabilizer Combinations: A Review of Safety and Efficacy
Authors: Marlene P. Freeman, Andrew L. Stoll
Journal: American Journal of Psychiatry (1998)

OBJECTIVE: Polypharmacy is common in the treatment of refractory bipolar disorder. The purpose of this article is to review the safety and efficacy of mood stabilizers in combinations. METHOD: A manual and computer (MEDLINE) search was performed for combinations of the most commonly used mood-stabilizing agents. RESULTS: The authors review safety and efficacy data on the more frequently encountered combinations of established and putative mood stabilizers. CONCLUSIONS: There have been few controlled studies of the use of combinations of mood stabilizers. The interactions of such combinations are sometimes complex, often very useful, and potentially dangerous. One general rule that may reduce the risks of toxic drug interactions is to add medication to the patient's current regimen in modest doses and increase the dose slowly. The safest and most efficacious mood stabilizer combinations appear to be the mixtures of anticonvulsants and lithium, particularly valproate plus lithium. Once the mechanisms of the mood stabilizers are identified, it is possible that a more rational approach to combination therapy will emerge, based on synergism at the sites of action. (Am J Psychiatry 1998; 155:12–21)
The gain and loss of genes during 600 million years of vertebrate evolution.
Authors: Tine Blomme, Klaas Vandepoele, Stefanie De Bodt, Cedric Simillion, Steven Maere, Yves Van de Peer
Journal: Genome biology (2006)

Abstract Background Gene duplication is assumed to have played a crucial role in the evolution of vertebrate organisms. Apart from a continuous mode of duplication, two or three whole genome duplication events have been proposed during the evolution of vertebrates, one or two at the dawn of vertebrate evolution, and an additional one in the fish lineage, not shared with land vertebrates. Here, we have studied gene gain and loss in seven different vertebrate genomes, spanning an evolutionary period of about 600 million years. Results We show that: first, the majority of duplicated genes in extant vertebrate genomes are ancient and were created at times that coincide with proposed whole genome duplication events; second, there exist significant differences in gene retention for different functional categories of genes between fishes and land vertebrates; third, there seems to be a considerable bias in gene retention of regulatory genes towards the mode of gene duplication (whole genome duplication events compared to smaller-scale events), which is in accordance with the so-called gene balance hypothesis; and fourth, that ancient duplicates that have survived for many hundreds of millions of years can still be lost. Conclusion Based on phylogenetic analyses, we show that both the mode of duplication and the functional class the duplicated genes belong to have been of major importance for the evolution of the vertebrates. In particular, we provide evidence that massive gene duplication (probably as a consequence of entire genome duplications) at the dawn of vertebrate evolution might have been particularly important for the evolution of complex vertebrates.
Expression of macrophage migration inhibitory factor in diffuse systemic sclerosis
Authors: E Selvi
Journal: Annals of the Rheumatic Diseases (2003)

To evaluate whether, in patients with the diffuse form of systemic sclerosis (dSSc), macrophage migration inhibitory factor (MIF) production is dysregulated.10 patients with dSSc and 10 healthy controls, matched for age and sex, were studied. MIF expression was evaluated by immunohistochemistry on formalin fixed skin biopsies of patients with dSSc and controls. MIF levels were assayed in the sera and in the supernatants of skin cultured fibroblasts by a colorimetric sandwich enzyme linked immunosorbent assay (ELISA). MIF concentrations in culture medium samples and in serum samples were compared by Student's two tailed t test for unpaired data.Anti-MIF antibody immunostained the basal and mainly suprabasal keratinocytes. Small perivascular clusters of infiltrating mononuclear cells were positive; scattered spindle fibroblast-like cells were immunostained in superficial and deep dermal layers. The serum concentrations of MIF in patients with dSSc (mean (SD) 10705.6 (9311) pg/ml) were significantly higher than in controls (2157.5 (1288.6) pg/ml; p=0.011); MIF levels from dSSc fibroblast cultures (mean (SD) 1.74 (0.16) ng/2 x 10(5) cells) were also significantly higher than in controls (0.6 (0.2) ng/2 x 10(5) cells; p=0.008).These results suggest that MIF may be involved in the amplifying proinflammatory loop leading to scleroderma tissue remodelling.
Hepatic arterial infusion (HAI) therapy in patients with unresectable primary liver cancer: Use of dynamic contrast enhanced MRI to evaluate response
Authors: M. Danso, W. R. Jarnagin, M. Muruganandham, L. H. Schwartz, M. Gonen, D. Haviland, L. Blumgart, M. D’Angelica, R. Dematteo, N. Kemeny
Journal: Journal of Clinical Oncology (2005)

4129 Background: This study reports preliminary results of the use of HAI of Floxuridine (FUDR) and Dexamethasone (Dex) in patients (pts) with unresectable cholangiocarcinoma (CC) or hepatocellular cancer (HCC), and investigates the use of dynamic contrast-enhanced MRI (DCE-MRI) to evaluate changes in tumor perfusion, and to correlate these findings with radiographic tumor response. Methods: Seventeen pts (15 CC, 2 HCC) deemed unresectable by experienced hepatobiliary surgeons were treated with HAI FUDR/Dex via arterial pump by continuous infusion over 14 days on a 4-week cycle. Imaging: MRI imaging was performed on a conventional 1.5 Tesla MRI scanner. DCE-MRI images were acquired with a temporal resolution of 1 second per image. Analysis was performed with a two compartment model, the slope of the initial contrast uptake, as well as transfer between lesion and plasma compartments were calculated. Results: Of 17 pts, 14 are presently evaluable, while 3 are too early to assess for response. One of 2 pts with HCC responded; 5 of 12 pts (42%) with CC had partial response, and 6 (50%) had stable disease. Median duration of response is 11.9 months (range 4.1 - 14.7). Median time to progression for all pts is 7.2 months. Seven have progressed: 4 (liver), 2 (lung), 1 (bone). Treatment has been well-tolerated: Gr 3 SGOT elevation was seen in 5 pts (29%), and Gr 3 alkaline phosphatase in 4 (23%). No pt had bilirubin elevation, diarrhea or neutropenia. Comparison of lesion size on DCE-MRI and conventional MRI showed that post-treatment changes in tumor perfusion (slope measurements) observed at 2 months predict treatment response earlier than bi-dimensional tumor measurements. Patients with rapid uptake of contrast (slope > 300% increase/min) all showed tumor response. Conclusions: Presently, HAI therapy with FUDR + Dex demonstrates a 43% response rate with an excellent toxicity profile. Changes in tumor perfusion and vascular permeability may predict treatment response earlier and correlate with probability of response in pts with CC or HCC. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Johnson & Johnson Johnson & Johnson
The social aetiology of essentialist beliefs
Authors: Cliodhna O'Connor, Helene Joffe
Journal: Behavioral and Brain Sciences (2014)

Abstract This commentary highlights the importance of attending to the sociocultural contexts that foster essentialist ideas. It contends that Cimpian &amp; Salomon's (C&amp;S's) model undervalues the extent to which the development of essentialist beliefs is contingent on social experience. The result is a restriction of the model's applicability to real-world instances of essentialism-fuelled prejudice and discrimination.
How do GPs use x rays to manage chronic knee pain in the elderly? A case study
Authors: J Bedson
Journal: Annals of the Rheumatic Diseases (2003)

To determine whether clinical signs and symptoms of osteoarthritis influence general practitioners' (GPs) decisions about x raying older patients with knee pain and whether x ray reports alter their initial treatment or referral plan.A cross sectional survey of 1000 GPs in England and Wales using "paper cases" in three questionnaires mailed at two-weekly intervals. The first questionnaire assessed GPs' management of patients with knee pain using four case scenarios, two with features of clinical knee osteoarthritis. The second questionnaire contained the same scenarios with information on x ray findings added. The third questionnaire considered management of knee pain in general.447 GPs responded to questionnaire 1, 316 (71%) to questionnaire 2, 287 (64%) to questionnaire 3. 106 responders (25%) would have x rayed all four patients and 64 (15%) none. Choosing to carry out an x ray examination was not influenced by the presence of clinical signs and symptoms of osteoarthritis but was linked to other management choices, such as referral to orthopaedics (odds ratio (OR) 2.13; 95% confidence interval (CI) 1.62 to 2.81). The strongest predictor in questionnaire 2 of a treatment or referral was whether it had been chosen in the first survey. However, the x ray report was associated with a significant change in treatment and referrals. Where radiographic osteoarthritis was present, GPs were less likely to refer to a physiotherapist (OR 0.64; 95% CI 0.50 to 0.83) or rheumatologist (OR 0.15; 95% CI 0.08 to 0.28), and more likely to refer to an orthopaedic surgeon (OR 31.34; 95% CI 21.51 to 45.66). Questionnaire 3 showed that GPs' general views on the use of x rays correlated with the frequency of their choosing to x ray in the four individual case scenarios.A GP's choice to x ray older people with knee symptoms is linked with decisions on treatment and referral even before the x ray result is known, but it does not appear to be influenced by clinical features of osteoarthritis. The presence of radiographic osteoarthritis has a marked impact on the decision to refer to secondary care. More evidence on the outcome of management without x rays is needed to help GPs in decision making.
Screening for NIDDM in Nonpregnant Adults: A review of principles, screening tests, and recommendations
Authors: Michael M Engelgau, Ronald E Aubert, Theodore J Thompson, William H Herman
Journal: Diabetes Care (1995)

The economic burden of diabetes in the U.S. is now more than 90 billion dollars per year (113-115). In the diabetes community, there is a feeling that aggressive measures to detect diabetes in earlier stages may be warranted. Regardless of whether evidence is convincing that there are benefits from early detection of diabetes (3,116,117), screening activities have been sanctioned by many organizations and are now taking place. Operational research is needed to define more clearly the who, when, where, and how of screening and the effectiveness of screening programs (4,118). Diabetes screening programs should be comprehensive and should educate about diabetes and provide appropriate interpretation of both positive and negative screening results. It is essential that programs have diagnostic follow-up and refer those with newly diagnosed diabetes for treatment. In addition, individuals with previously diagnosed diabetes encountered during screening activities should be made aware of the importance of glycemic control and follow-up with their health care providers.