tbuckley/cabot-search huggingface dataset:
Like father, like son
Authors: J. Lee, P. Merry, R. Ball, K. Gaffney
Journal: Annals of the Rheumatic Diseases (2007)

within 2 weeks.Sixteen per cent of respondents would treat asymptomatic hyperuricaemia with ULT, with a marked difference in practice being observed between rheumatologists and internal medicine specialists (15% versus 59%, respectively).Importantly, opinions varied considerably on what sUA level might be regarded as representing adequate control in a gout patient (fig 1).It is interesting to consider some of these findings in light of the recent EULAR recommendations.These make clear, for example, that sUA levels do not confirm or exclude a diagnosis of gout.Despite this, nearly all respondents (97%) stated that they would rely on measuring sUA for precisely that purpose.For gout management the recommendations assign a central role to sUA and define the therapeutic goal of ULT as being to promote crystal dissolution, prevent crystal formation and improve clinical symptoms by maintaining sUA below 6 mg/dl.The survey findings show, however, that most physicians perceive a reduction in the frequency of acute attacks as the central goal of therapy and that the ability to cure the condition by maintaining sUA below 6 mg/dl is not yet universally appreciated.A caveat of any such survey is that physicians may have responded on the basis of what they know should be done rather than what they actually do in practice.They may also have completed the survey in haste and possibly misinterpreted some of the questions.Nevertheless, a large number of practitioners representing several countries in Europe participated in this simple survey.The authors hope that, as awareness of the EULAR recommendations grows, and the goal of maintaining sUA below 6 mg/dl becomes more widely recognised, all patients with gout will be spared the burden of this eminently treatable condition.
Elevated expression and polymorphisms of SOCS3 influence patient response to antiviral therapy in chronic hepatitis C
Authors: M Persico, M Capasso, R Russo, E Persico, L Croce, C Tiribelli, A Iolascon
Journal: Gut (2007)

The response to antiviral therapy of chronic hepatitis C virus (HCV) infection is determined by virological, environmental and genetic factors.The hypothesis was tested that the expression of specific genes and their haplotype frequencies can differentiate between non-responders (NRs) and sustained virological responders (SVRs) to antiviral treatment.A methodological approach based on molecular marker discovery and validation was used to study the genes influencing the antiviral treatment in lymphoblastoid cell lines from 74 genotype 1b HCV patients (44 from Southern Italy and 30 from Northern Italy) treated with pegylated interferon (IFN) alpha and ribavirin. Furthermore, an association study was performed, testing three single nucleotide polymorphisms (SNPs) of suppressor of cytokine signalling 3 (SOCS3) in 162 NR and 184 SVR subjects (SOCS3 -8464 A/C (rs12952093), -4874 A/G (rs4969170) and 1383 A/G, (rs4969168)).SOCS3 basal expression levels were significantly increased in two independent sets of NR groups (p<0.05). A highly significant association was found between NRs and both the positively associated haplotype (OR = 2.01, 95% CI 1.45 to 2.79, p = 0.0002) and the negatively associated haplotype (OR = 0.56, 95% CI 0.42 to 0.76, p = 0.0014). In particular, the SOCS3 -4874 AA genotype was strongly associated with failure of antiviral therapy (OR = 4.00, 95% CI 2.09 to 7.66, p = 0.0003) and the AA genotype carriers had significantly higher SOCS3 mRNA and protein levels (p<0.05).Basal levels of SOCS3, an inhibitor of the IFN alpha-induced Janus kinase-signal transducer and activator of transcription pathways, and its genetic polymorphisms influence the outcome of antiviral treatment. SOCS3 thus represents a novel blood biomarker for the a priori prediction of treatment response.
Transgenic Remodeling of the Regulatory Myosin Light Chains in the Mammalian Heart
Authors: James Gulick, Timothy E. Hewett, Raisa Klevitsky, Scott H. Buck, Richard L. Moss, Jeffrey Robbins
Journal: Circulation Research (1997)

Abstract The regulatory myosin light chain (MLC) regulates contraction in smooth muscle. However, its function in striated muscle remains obscure, and the different functional activities of the various isoforms that are expressed in the mammalian heart (ventricle- and atrium-specific MLC2) remain undefined. To begin to explore these issues, we used transgenesis to determine the feasibility of effecting a complete or partial replacement of the cardiac regulatory light chains with the isoform that is normally expressed in fast skeletal muscle fibers (fast muscle–specific MLC2). Multiple lines of transgenic mice were generated that expressed the transgene at varying levels in the heart in a copy number–dependent fashion. There is a major discordance in the manner in which the different cardiac compartments respond to high levels of overexpression of the transgene. In atria, isoform replacement with the skeletal protein was quite efficient, even at low copy number. The ventricle is much more refractory to replacement, and despite high levels of transgenic transcript, protein replacement was incomplete. Replacement could be further increased by breeding the transgenic lines with one another. Despite very high levels of transgenic transcript in these mice, the overall level of the regulatory light chain in both compartments remained essentially constant; only the protein isoform ratios were altered. The partial replacement of the ventricular with the skeletal isoform reduced both left ventricular contractility and relaxation, although the unloaded shortening velocity of isolated ventricular cardiomyocytes was not significantly different.
Rapid Molecular Screening for Multidrug-Resistant Tuberculosis in a High-Volume Public Health Laboratory in South Africa
Authors: Marinus Barnard, Heidi Albert, Gerrit Coetzee, Richard O'Brien, Marlein E Bosman
Journal: American Journal of Respiratory and Critical Care Medicine (2008)

The dual challenges to tuberculosis (TB) control of HIV infection and multidrug resistance are particularly pressing in South Africa. Conventional methods for detecting Mycobacterium tuberculosis drug resistance take weeks to months to produce results. Rapid molecular testing for drug resistance is available but has not been implemented in high-TB-burden settings.To assess the performance and feasibility of implementation of a commercially available molecular line-probe assay for rapid detection of rifampicin and isoniazid resistance.We performed the assay directly on 536 consecutive smear-positive sputum specimens from patients at increased risk of multidrug-resistant (MDR) TB in a busy routine diagnostic laboratory in Cape Town, South Africa. Results were compared with conventional liquid culture and drug susceptibility testing on solid medium.Overall, 97% of smear-positive specimens gave interpretable results within 1-2 days using the molecular assay. Sensitivity, specificity, and positive and negative predictive values were 98.9, 99.4, 97.9, and 99.7%, respectively, for detection of rifampicin resistance; 94.2, 99.7, 99.1, and 97.9%, respectively, for detection of isoniazid resistance; and 98.8, 100, 100, and 99.7%, respectively, for detection of multidrug resistance compared with conventional results. The assay also performed well on specimens that were contaminated on conventional culture and on smear-negative, culture-positive specimens.This molecular assay is a highly accurate screening tool for MDR TB, which achieves a substantial reduction in diagnostic delay. With overall performance characteristics that are superior to conventional culture and drug susceptibility testing and the possibility for high throughput with substantial cost savings, molecular testing has the potential to revolutionize MDR TB diagnosis.
Association of Merkel Cell Polyomavirus–Specific Antibodies With Merkel Cell Carcinoma
Authors: Joseph J. Carter, Kelly G. Paulson, Greg C. Wipf, Danielle Miranda, Margaret M. Madeleine, Lisa G. Johnson, Bianca D. Lemos, Sherry Lee, Ashley H. Warcola, Jayasri G. Iyer, Paul Nghiem, Denise A. Galloway
Journal: JNCI Journal of the National Cancer Institute (2009)

BackgroundMerkel cell polyomavirus (MCPyV) has been detected in approximately 75% of patients with the rare skin cancer Merkel cell carcinoma. We investigated the prevalence of antibodies against MCPyV in the general population and the association between these antibodies and Merkel cell carcinoma.
Molecular Alterations in Primary Prostate Cancer after Androgen Ablation Therapy
Authors: Carolyn J.M. Best, John W. Gillespie, Yajun Yi, Gadisetti V.R. Chandramouli, Mark A. Perlmutter, Yvonne Gathright, Heidi S. Erickson, Lauren Georgevich, Michael A. Tangrea, Paul H. Duray, Sergio González, Alfredo Velasco, W. Marston Linehan, Robert J. Matusik, Douglas K. Price, William D. Figg, Michael R. Emmert-Buck, Rodrigo F. Chuaqui
Journal: Clinical Cancer Research (2005)

Abstract Purpose: After an initial response to androgen ablation, most prostate tumors recur, ultimately progressing to highly aggressive androgen-independent cancer. The molecular mechanisms underlying progression are not well known in part due to the rarity of androgen-independent samples from primary and metastatic sites. Experimental Design: We compared the gene expression profiles of 10 androgen-independent primary prostate tumor biopsies with 10 primary, untreated androgen-dependent tumors. Samples were laser capture microdissected, the RNA was amplified, and gene expression was assessed using Affymetrix Human Genome U133A GeneChip. Differential expression was examined with principal component analysis, hierarchical clustering, and Student's t testing. Analysis of gene ontology was done with Expression Analysis Systematic Explorer and gene expression data were integrated with genomic alterations with Differential Gene Locus Mapping. Results: Unsupervised principal component analysis showed that the androgen-dependent and androgen-independent tumors segregated from one another. After filtering the data, 239 differentially expressed genes were identified. Two main gene ontologies were found discordant between androgen-independent and androgen-dependent tumors: macromolecule biosynthesis was down-regulated and cell adhesion was up-regulated in androgen-independent tumors. Other differentially expressed genes were related to interleukin-6 signaling as well as angiogenesis, cell adhesion, apoptosis, oxidative stress, and hormone response. The Differential Gene Locus Mapping analysis identified nine regions of potential chromosomal deletion in the androgen-independent tumors, including 1p36, 3p21, 6p21, 8p21, 11p15, 11q12, 12q23, 16q12, and 16q21. Conclusions: Taken together, these data identify several unique characteristics of androgen-independent prostate cancer that may hold potential for the development of targeted therapeutic intervention.
Drug Hypersensitivity and Human Leukocyte Antigens of the Major Histocompatibility Complex
Authors: Mandvi Bharadwaj, Patricia Illing, Alex Theodossis, Anthony W. Purcell, Jamie Rossjohn, James McCluskey
Journal: The Annual Review of Pharmacology and Toxicology (2011)

The human leukocyte antigen (HLA) genes are the most polymorphic in the human genome and are critical in regulating specific immunity, hence their historical discovery as “immune response” genes. HLA allotypes are also implicated in unwanted immune reactions, including drug hypersensitivity syndrome, in which small therapeutic drugs interact with antigenic peptides to drive T cell responses restricted by host HLA. Abacavir, allo-purinol, and carbamazepine are three commonly used drugs that cause a T cell–mediated hypersensitivity that is HLA linked, with each drug exhibiting striking specificity for presentation by defined HLA allotypes. Recent findings have begun to unearth the mechanistic basis for these HLA associations, and here we review recent advances in the field of HLA-associated drug hypersensitivities.
External-Beam Accelerated Partial-Breast Irradiation: Exploring the Limits of Tolerability
Authors: Reshma Jagsi, Bruce G. Haffty
Journal: Journal of Clinical Oncology (2013)

Radiation therapy is a critical element of breast-conserving therapy that has been shown to yield a substantial improvement in local control and a modest improvement in survival. 1 In most studies of adjuvant radiotherapy after breast-conserving surgery, standard fractionation, with doses of 1.8 to 2.0 Gy per treatment, has been used to administer treatment to the whole breast, once a day. This approach relies on the radiobiologic rationale that slowly dividing cells of normaltissuescanrepairradiation-induceddamagebetweensmall daily fractions in a way that rapidly dividing tumor cells, which are often characterized by deficiencies in DNA repair, cannot. Thus, fractionation of dose contributes to the therapeutic ratio of radiation treatment. Because 5 to 6 weeks of standard fractionated treatment are necessary to reach total doses that generally control microscopic disease,concernshavearisenregardingtheconvenience,access,andcost of this approach. At the same time, evidence has emerged to suggest that breast cancer cells may be more sensitive to larger fraction sizes than previously thought, suggesting that lower total doses of radiotherapy may be equally efficacious if treatment is administered in larger daily fractions. Therefore, interest in hypofractionated schedules of breast irradiation has grown in recent years. Severalstudieshaveexploredavarietyofschedulesforhypofractionated whole-breast irradiation, including a Canadian randomized trial that reported equivalent efficacy and toxicity at 10 years from a schedule of 42.5 Gy in 16 fractions compared with 50 Gy in 25 fractions. 2 Randomized trials from the United Kingdom have also demonstrated equivalent outcomes comparing standard whole-breast irradiation with hypofractionated whole-breast irradiation. 3,4 Others have been motivated to explore treatment to only part of the breast, inspiredbyfindingsthatsuggestthatthemajorityoflocalrecurrences after breast-conserving surgery occur in the region of the tumor bed.
Effects of Survivin Antagonists on Growth of Established Tumors and B7-1 Immunogene Therapy
Authors: J. R. Kanwar, W.-P. Shen, R. K. Kanwar, R. W. Berg, G. W. Krissansen
Journal: JNCI Journal of the National Cancer Institute (2001)

Background: Survivin, a member of the inhibitor of apoptosis (IAP) protein family, is detectable in most types of cancer, and its presence is associated with a poor prognosis. We determined the effects of gene-based therapies that inhibit survivin function in a mouse tumor model. Methods: Using five to six mice per treatment group, we injected tumors derived from mouse EL-4 thymic lymphoma cells with plasmids encoding antisense survivin, a dominant-negative mutant survivin, and the T-cell costimulator B7-1. Expression of endogenous survivin and the proteins encoded by the injected plasmids were examined by immunohistochemical staining of tumor sections and by western blot and flow cytometry analyses of isolated tumor cells. Tumor growth, the generation of antitumor cytotoxic T-lymphocyte (CTL) activity, apoptosis, and the contribution of leukocyte subsets to antitumor activity were measured. All statistical tests were two-sided. Results: Large (1.0-cm diameter) tumors had approximately 10-fold more survivin than small (0.2-cm diameter) tumors. At 28 days after injection, antisense and dominant-negative mutant survivin plasmids statistically significantly inhibited the growth of both small (P = .006 and P = .0018, respectively) and large (P<.001 for both plasmids) EL-4 tumors compared with tumors injected with empty plasmid. The growth of large tumors was further inhibited by intratumoral injection with antisense survivin and B7-1 (P = .004); thus, inhibition of survivin expression renders large tumors susceptible to B7-1-mediated immunotherapy. Mice whose tumors were completely eradicated by injection of B7-1 remained tumor free for 26 days after re-injection with EL-4 cells (when the experiment ended). Compared with tumors injected with empty plasmid, tumors injected with survivin-based plasmids had increased apoptosis, and animals bearing such tumors generated more antitumor CTLs. Conclusion: Intratumoral injection of plasmids that block survivin expression and stimulate the generation of tumor-specific CTLs may be beneficial for the treatment of large lymphomas.
Evidence for Basolateral P2Y6 Receptors along the Rat Proximal Tubule
Authors: MATTHEW A. BAILEY, MARTINE IMBERT-TEBOUL, CLARE TURNER, S. KAILA SRAI, GEOFFREY BURNSTOCK, ROBERT J. UNWIN
Journal: Journal of the American Society of Nephrology (2001)

Abstract. In this study, the distribution of P2Y 6 receptor mRNA in rat nephron segments was investigated and a functional approach was used to analyze basolateral protein expression. Reverse transcription-PCR studies revealed more intense expression of P2Y 6 receptor mRNA in the proximal tubule and the thick ascending limb of Henle's loop, less intense expression in the thin descending limb and the cortical and outer medullary collecting ducts, and no detectable expression in either the thin ascending limb or the inner medullary collecting duct. Dose-dependent calcium responses to basolateral administration of UDP (a selective agonist for the P2Y 6 receptor) were observed in the proximal tubule but not in any of the other segments studied. In the proximal tubule, intracellular calcium concentration changes induced by UDP were associated with increased production of inositol phosphates, as were those induced by ATP and norepinephrine. However, UDP-induced intracellular calcium concentration changes were different, exhibiting no plateau after the initial peak; moreover, a single stimulation with a high concentration of UDP induced full desensitization of the UDP-sensitive calcium pathway but did not alter the responsiveness of the proximal tubule to ADP (a specific P2Y 1 receptor agonist), ATP or norepinephrine. In summary, this report demonstrates that P2Y 6 receptor mRNA is expressed in most segments of the rat nephron but that basolateral expression of the protein is restricted to the proximal tubule, where the receptor is coexpressed with the P2Y 1 receptor. The differences in the distributions of P2Y 6 receptor mRNA and UDP responses may indicate the presence of luminal receptors in other nephron segments.
Mapping Human Genetic Ancestry
Authors: I. Ebersberger, P. Galgoczy, S. Taudien, S. Taenzer, M. Platzer, A. von Haeseler
Journal: Molecular Biology and Evolution (2007)

The human genome is a mosaic with respect to its evolutionary history. Based on a phylogenetic analysis of 23,210 DNA sequence alignments from human, chimpanzee, gorilla, orangutan, and rhesus, we present a map of human genetic ancestry. For about 23% of our genome, we share no immediate genetic ancestry with our closest living relative, the chimpanzee. This encompasses genes and exons to the same extent as intergenic regions. We conclude that about 1/3 of our genes started to evolve as human-specific lineages before the differentiation of human, chimps, and gorillas took place. This explains recurrent findings of very old human-specific morphological traits in the fossils record, which predate the recent emergence of the human species about 5-6 MYA. Furthermore, the sorting of such ancestral phenotypic polymorphisms in subsequent speciation events provides a parsimonious explanation why evolutionary derived characteristics are shared among species that are not each other's closest relatives.
Glucocorticoid levels in maternal and cord serum after prenatal betamethasone therapy to prevent respiratory distress syndrome.
Authors: P L Ballard, P Granberg, R A Ballard
Journal: Journal of Clinical Investigation (1975)

Serum glucocorticoid levels were determined in 20 mothers and 43 premature infants who received prenatal betamethasone therapy for prevention of respiratory distress syndrome (RDS). Maternal betamethasone peaked at 75 microg cortisol equivalents per 100 ml 1 h after injection of 12 mg steroid and declined to half by 6 h. Betamethasone in cord blood was 14.3 microg cortisol equivalents per 100 ml at 1 h, decreased to a level of 4.7 at 20 h, and was not detected 2 days after a second dose at 24 h. After the second dose, the mean level of cortisol in cord blood was 5.9 microg per 100 ml compared with 13.05 microg per 100 ml (p less than 0.001) in untreated premature infants. The unbound glucocorticoid activity in treated infants delivered 1-10 h after the second dose (mean, 8.4 microg per 100 ml) is similar to the unbound cortisol level after birth in untreated premature infants who develop RDS. These findings indicate that (a) serum glucocorticoid levels in the physiologic stress range can induce lung maturation in the human and (b) antenatal treatment with this dose of betamethasone does not expose the human fetus to potentially harmful pharmacologic levels of steroid.
Clinical signs and symptoms of oropharyngeal aspiration and dysphagia in children
Authors: K. Weir, S. McMahon, L. Barry, I. B. Masters, A. B. Chang
Journal: European Respiratory Journal (2008)

The diagnostic value of various signs and symptoms (clinical markers) in predicting oropharyngeal aspiration (OPA) or swallowing dysfunction has not been established in children. The present retrospective study was undertaken to: 1) identify specific clinical markers associated with radiographic evidence of OPA, isolated laryngeal penetration (ILP) and post-swallow residue (PSR); 2) determine the sensitivity and specificity of clinical markers associated with OPA; and 3) determine the influence of age and neurological impairment on clinical markers of OPA. In total, 11 clinical markers of dysphagia were compared with the videofluoroscopic swallow study (VFSS) results (OPA, ILP and PSR) in 150 children on diets of thin fluid and purée consistencies. Chi-squared and logistic regression were used to analyse the association between clinical markers and VFSS-identified swallowing dysfunction. In children with OPA, wet voice (odds ratio (OR) 8.90, 95% confidence interval (CI) 2.87-27.62), wet breathing (OR 3.35, 95% CI 1.09-10.28) and cough (OR 3.30, 95% CI 1.17-9.27) were significantly associated with thin fluid OPA. Predictive values included: wet voice (sensitivity 0.67; specificity 0.92); wet breathing (sensitivity 0.33; specificity 0.83); and cough (sensitivity 0.67; specificity 0.53). No clinical markers were significantly associated with OPA, ILP or PSR on the purée consistency. Cough was significantly associated with PSR on thin fluids (OR 3.59, 95% CI 1.22-10.55). Differences were found for age. Wet voice, wet breathing and cough were good clinical markers for children with oropharyngeal aspiration on thin fluid but not on purée. Age and neurological status influenced the significance of these clinical markers.