tbuckley/cabot-search huggingface dataset:
Measuring quality of care for rheumatic diseases using an electronic medical record
Authors: J C Agnew-Blais, J S Coblyn, J N Katz, R J Anderson, J Mehta, D H Solomon
Journal: Annals of the Rheumatic Diseases (2008)

The objective of this study was twofold: (1) to determine how best to measure adherence with time-dependent quality indicators (QIs) related to laboratory monitoring, and (2) to assess the accuracy and efficiency of gathering QI adherence information from an electronic medical record (EMR).A random sample of 100 patients were selected who had at least three visits with the diagnosis of rheumatoid arthritis (RA) at Brigham and Women's Hospital Arthritis Center in 2005. Using the EMR, it was determined whether patients had been prescribed a disease-modifying antirheumatic drug (DMARD) (QI #1) and if patients starting therapy received appropriate baseline laboratory testing (QI #2). For patients consistently prescribed a DMARD, adherence with follow-up testing (QI #3) was calculated using three different methods, the Calendar, Interval and Rolling Interval.It was found that 97% of patients were prescribed a DMARD (QI #1) and baseline tests were completed in 50% of patients (QI #2). For follow-up testing (QI #3), mean adherence was 60% for the Calendar Method, 35% for the Interval Method, and 48% for the Rolling Interval Method. Using the Rolling Interval Method, adherence rates were similar across drug and laboratory testing type.Results for adherence with laboratory testing QIs for DMARD use differed depending on how the QIs were measured, suggesting that care must be taken in clearly defining methods. While EMRs will provide important opportunities for measuring adherence with QIs, they also present challenges that must be examined before widespread adoption of these data collection methods.
Antisense Oligonucleotide-induced Exon Skipping Across the Human Dystrophin Gene Transcript
Authors: Steve D Wilton, Abbie M Fall, Penny L Harding, Graham McClorey, Catherine Coleman, Susan Fletcher
Journal: Molecular Therapy (2007)

Protein-truncating mutations in the dystrophin gene lead to the most common childhood form of muscle wasting, Duchenne muscular dystrophy. Becker muscular dystrophy, a condition that typically arises from dystrophin gene lesions that do not disrupt the reading frame, clearly indicates that substantial domains of the dystrophin protein are not essential. Potential therapeutic intervention exists during pre-mRNA splicing, whereby selected exons are excised to either remove nonsense mutations or restore the reading frame around frame-shifting mutations from the mature mRNA. Appropriately designed antisense oligonucleotides (AOs), directed at amenable splicing motifs across the dystrophin gene transcript, block exon recognition and/or spliceosome assembly so that targeted exons are removed from the mature mRNA. We describe a panel of AOs designed to induce skipping of every exon within the human dystrophin gene transcript, with the exception of the first and last exons. Every exon targeted in vitro could be removed from the dystrophin mRNA, although some exons are more efficiently excluded than others. No single motif has emerged as a universal AO annealing site for redirection of dystrophin pre-mRNA processing, although the general trend is that the most efficient compounds are directed at motifs in the first half of the target exon. Protein-truncating mutations in the dystrophin gene lead to the most common childhood form of muscle wasting, Duchenne muscular dystrophy. Becker muscular dystrophy, a condition that typically arises from dystrophin gene lesions that do not disrupt the reading frame, clearly indicates that substantial domains of the dystrophin protein are not essential. Potential therapeutic intervention exists during pre-mRNA splicing, whereby selected exons are excised to either remove nonsense mutations or restore the reading frame around frame-shifting mutations from the mature mRNA. Appropriately designed antisense oligonucleotides (AOs), directed at amenable splicing motifs across the dystrophin gene transcript, block exon recognition and/or spliceosome assembly so that targeted exons are removed from the mature mRNA. We describe a panel of AOs designed to induce skipping of every exon within the human dystrophin gene transcript, with the exception of the first and last exons. Every exon targeted in vitro could be removed from the dystrophin mRNA, although some exons are more efficiently excluded than others. No single motif has emerged as a universal AO annealing site for redirection of dystrophin pre-mRNA processing, although the general trend is that the most efficient compounds are directed at motifs in the first half of the target exon.
Expression of the neuron-specific protein CHD5 is an independent marker of outcome in neuroblastoma
Authors: Idoia Garcia, Gemma Mayol, Eva Rodríguez, Mariona Suñol, Timothy R Gershon, José Ríos, Nai-Kong V Cheung, Mark W Kieran, Rani E George, Antonio R Perez-Atayde, Carla Casala, Patricia Galván, Carmen de Torres, Jaume Mora, Cinzia Lavarino
Journal: Molecular Cancer (2010)

Abstract Background The chromodomain, helicase DNA-binding protein 5 (CHD5) is a potential tumor suppressor gene located on chromosome 1p36, a region recurrently deleted in high risk neuroblastoma (NB). Previous data have shown that CHD5 mRNA is present in normal neural tissues and in low risk NB, nevertheless, the distribution of CHD5 protein has not been explored. The aim of this study was to investigate CHD5 protein expression as an immunohistochemical marker of outcome in NB. With this purpose, CHD5 protein expression was analyzed in normal neural tissues and neuroblastic tumors (NTs). CHD5 gene and protein expression was reexamined after induction chemotherapy in a subset of high risk tumors to identify potential changes reflecting tumor response. Results We provide evidence that CHD5 is a neuron-specific protein, absent in glial cells, with diverse expression amongst neuron types. Within NTs, CHD5 immunoreactivity was found restricted to differentiating neuroblasts and ganglion-like cells, and absent in undifferentiated neuroblasts and stromal Schwann cells. Correlation between protein and mRNA levels was found, suggesting transcriptional regulation of CHD5 . An immunohistochemical analysis of 90 primary NTs highlighted a strong association of CHD5 expression with favorable prognostic variables (age at diagnosis &lt;12 months, low clinical stage, and favorable histology; P &lt; 0.001 for all), overall survival (OS) (P &lt; 0.001) and event-free survival (EFS) (P &lt; 0.001). Multivariate analysis showed that CHD5 prognostic value is independent of other clinical and biologically relevant parameters, and could therefore represent a marker of outcome in NB that can be tested by conventional immunohistochemistry. The prognostic value of CHD5 was confirmed in an independent, blinded set of 32 NB tumors (P &lt; 0.001). Reactivation of CHD5 expression after induction chemotherapy was observed mainly in those high risk tumors with induced tumor cell differentiation features. Remarkably, these NB tumors showed good clinical response and prolonged patient survival. Conclusions The neuron-specific protein CHD5 may represent a marker of outcome in NB that can be tested by conventional immunohistochemistry. Re-establishment of CHD5 expression induced by chemotherapy could be a surrogate marker of treatment response.
Mild hyperthermia triggered doxorubicin release from optimized stealth thermosensitive liposomes improves intratumoral drug delivery and efficacy
Authors: Li Li, Timo L.M. ten Hagen, Martin Hossann, Regine Süss, Gerard C. van Rhoon, Alexander M.M. Eggermont, Dieter Haemmerich, Gerben A. Koning
Journal: Journal of Controlled Release (2013)
Urbanicity and Lifestyle Risk Factors for Cardiometabolic Diseases in Rural Uganda: A Cross-Sectional Study
Authors: Johanna Riha, Alex Karabarinde, Gerald Ssenyomo, Steven Allender, Gershim Asiki, Anatoli Kamali, Elizabeth H. Young, Manjinder S. Sandhu, Janet Seeley
Journal: PLoS Medicine (2014)

Johanna Riha and colleagues evaluate the association of lifestyle risk factors with elements of urbanicity, such as having a public telephone, a primary school, or a hospital, among individuals living in rural settings in Uganda. Please see later in the article for the Editors' Summary
Selective Targeting and Potent Control of Tumor Growth Using an EphA2/CD3-Bispecific Single-Chain Antibody Construct
Authors: Scott A. Hammond, Ralf Lutterbuese, Shannon Roff, Petra Lutterbuese, Bernd Schlereth, Elizabeth Bruckheimer, Michael S. Kinch, Steve Coats, Patrick A. Baeuerle, Peter Kufer, Peter A. Kiener
Journal: Cancer Research (2007)

The EphA2 receptor tyrosine kinase is frequently overexpressed and functionally altered in malignant cells and thus provides opportunities for selective targeting of tumor cells. We describe here the development of a novel, bispecific single-chain antibody (bscAb) referred to as bscEphA2xCD3. This molecule simultaneously targets EphA2 on tumor cells and the T-cell receptor/CD3 complex on T cells and possesses structural and functional characteristics of the recently developed BiTE technology. An EphA2-specific single-chain antibody was selected for recognition of an epitope that is preferentially exposed on malignant cells based on the concept of epitope exclusion; this was fused to a CD3-specific single-chain antibody to generate bscEphA2xCD3. The resultant bscAb redirected unstimulated human T cells to lyse EphA2-expressing tumor cells both in vitro and in vivo. In separate experiments, efficient tumor cell lysis was achieved in vitro at drug concentrations <or=1 microg/mL, at a low T-cell effector-to-tumor target cell ratio (1:1), and with tumor cells that possess few available binding sites (2,400 per cell) for bscEphA2xCD3. Time-lapsed microscopy revealed potent cytotoxic activity of bscEphA2xCD3-activated T cells against monolayers of malignant cells but not against monolayers of nontransformed EphA2-positive cells except at the edges of the monolayer where the target epitope was exposed. BscEphA2xCD3 was also efficacious in human xenograft mouse models modified to show human T-cell killing of tumors. Together, our results reveal opportunities for redirecting the potent activity of cytotoxic T cells towards tumor cells that express selectively accessible epitopes and establish EphA2-specific bscAb molecules as novel and potent therapeutics with selectivity for tumor cells.
Evaluation of bronchodilator responses in patients with "irreversible" emphysema
Authors: D E O'Donnell, L Forkert, K A Webb
Journal: European Respiratory Journal (2001)

Given the emerging physiological and clinical rationale for pharmacological lung-volume reduction, assessment of volume responses to bronchodilators is likely to be highly relevant in chronic obstructive pulmonary disease (COPD). The authors examined the magnitude of lung-volume reduction after acute bronchodilator treatment in patients with advanced emphysema. Eighty-four stable patients with emphysema (mean±sem forced expiratory volume in one second (FEV 1 ): 32±1% predicted) performed spirometry and body plethysmography before and 15–30 min after 200 µg salbutamol. Only irreversible patients with a postbronchodilator change in FEV 1 &lt;10% pred were considered in this study. Postsalbutamol, the majority of subjects (83%) had significant improvements in one or more lung volumes: on average, residual volume (RV), functional residual capacity (FRC), inspiratory capacity (IC), forced vital capacity and slow vital capacity changed by −18±2, −10±1, 8±1, 9±1 and 7±1% pred (p&lt;0.0005 each). Total lung capacity (TLC) decreased 0.12±0.04 L (p&lt;0.01). Change in IC reflected change in FRC (r=−0.60, p&lt;0.0005), but more strongly in the 57% of patients with no significant change in TLC (r=−0.93, p&lt;0.0005). The magnitude and frequency of volume responses were greatest in patients with the most severe COPD; for example, RV decreased by 0.51±0.09 L (23±4% pred) and 0.27±0.04 L (14±2% pred) in severe and moderate subgroups, respectively. Significant reductions in lung hyperinflation occurred in the absence of a change in forced expiratory volume in one second after low-dose salbutamol in a majority of patients with advanced emphysema; the greatest changes occurred in those with the most severe disease.
Colchicine stimulation of pyrogen production by human blood leukocytes.
Authors: P Bodel
Journal: The Journal of Experimental Medicine (1976)

The effect of colchicine, an anti-inflammatory agent, on endogenous pyrogen (EP) production by human blood leukocytes in vitro was examined. Colchicine not only failed to suppress EP production by human leukocytes stimulated by phagocytosis, but, in the absence of other stimuli, micromolar concentrations of the drug induced pyrogen production and release by both polymorphonuclear (PMN) and mononuclear leukocytes. The response was dose related, occurring at concentrations above 0.1 muM. Colcemid and vinblastine, other agents which bind to microtubular protein, also induced pyrogen release from human leukocytes, whereas lumicolchicine, a light-alerted derivative of colchicine without affinity for microtubules, was ineffective. Colchicine did not induce EP production by rabbit leukocytes, even at 100 muM concentration. Studies of the mechanism of PMN leukocyte activation by Colcemid indicated that although the time required for contact between drug and leukocyte was brief, pyrogen production and release did not begin for 6 or more hours. If added during this time, puromycin prevented subsequent production and release of pyrogen. These results indicated that agents which interfere with the assembly of microtubules induce EP production and secretion by human leukocytes in vitro.
Somatostatin receptor (SSTR) subtype-selective analogues differentially suppress in vitro growth hormone and prolactin in human pituitary adenomas. Novel potential therapy for functional pituitary tumors.
Authors: I Shimon, X Yan, J E Taylor, M H Weiss, M D Culler, S Melmed
Journal: Journal of Clinical Investigation (1997)

Previously, we have shown somatostatin receptor (SSTR) subtype-specific regulation of growth hormone (GH), thyroid-stimulating hormone, and prolactin (PRL) secretion in human fetal pituitary cultures, where GH and thyroid-stimulating hormone are mediated by both SSTR2 and SSTR5, whereas SSTR2 preferentially mediates PRL secretion. We now tested SSTR subtype-selective analogues in primary human GH- and PRL-secreting pituitary adenoma cultures. Analogue affinities determined by membrane radioligand binding in cells stably expressing human SSTR forms were either SSTR2 or SSTR5-selective. Analogues preferential either for SSTR2, including octreotide, lanreotide, and novel compounds with improved affinity for SSTR2, or new SSTR5-selective compounds suppressed GH in tumor cell cultures (up to 44% of control; P < 0.0005). However, novel analogues from both groups were 30-40% more potent than octreotide and lanreotide in suppressing GH (P < 0.05). Heterologous analogue combinations containing both SSTR2- and SSTR5-selective compounds were more potent in decreasing GH than analogues used alone (P < 0.05), or than combinations of compounds specific for the same receptor subtype (P < 0.005). In contrast, SSTR2-selective analogues did not suppress PRL release from six cultured prolactinomas studied. However, new SSTR5-selective analogues suppressed in vitro PRL secretion (30-40%; P < 0.05) in four of six prolactinomas. These results suggest that both SSTR2 and SSTR5 are involved in GH regulation in somatotroph adenoma cells, whereas SSTR5 exclusively regulates PRL secretion from prolactinoma cells. Thus, somatostatin analogues with improved selective binding affinity for these receptor subtypes may be effective in the treatment of either GH- or PRL-secreting adenomas.
Rational design of small molecules as vaccine adjuvants
Authors: Tom Y.-H. Wu, Manmohan Singh, Andrew T. Miller, Ennio De Gregorio, Francesco Doro, Ugo D’Oro, David A. G. Skibinski, M. Lamine Mbow, Simone Bufali, Ann E. Herman, Alex Cortez, Yongkai Li, Bishnu P. Nayak, Elaine Tritto, Christophe M. Filippi, Gillis R. Otten, Luis A. Brito, Elisabetta Monaci, Chun Li, Susanna Aprea, Sara Valentini, Samuele Calabrό, Donatello Laera, Brunella Brunelli, Elena Caproni, Padma Malyala, Rekha G. Panchal, Travis K. Warren, Sina Bavari, Derek T. O’Hagan, Michael P. Cooke, Nicholas M. Valiante
Journal: Science Translational Medicine (2014)

Small-molecule immune potentiators can be engineered to be potent adjuvants with localized innate immune activation and short in vivo residence times.
Behavioral Disinhibition and the Development of Early-Onset Addiction: Common and Specific Influences
Authors: William G. Iacono, Stephen M. Malone, Matt McGue
Journal: Annual Review of Clinical Psychology (2008)

Research on substance use disorders is often compartmentalized, focused on understanding addiction to one substance or substance class at a time. Although this approach has contributed significantly to knowledge about addictions, early-onset substance use disorders appear to share common etiology with each other and with other disorders, traits, behaviors, and endophenotypes associated with behavioral disinhibition. We propose that a common genetic liability to behavioral disinhibition underlies the co-occurrence of these externalizing attributes. This liability is expressed in part through brain mechanisms related to cognitive control, impulsivity, and sensitivity to reward, all of which are maturing during adolescence. During this important transitional period, problem behaviors emerge, including the initiation of substance use. Exposure to various environmental risks further amplifies the risk associated with the common liability, increasing the likelihood of addiction generally. Specific environmental and genetic factors ultimately contribute to the differentiation among externalizing disorders.
Elevated S-Phase Kinase-Associated Protein 2 Protein Expression in Acute Myelogenous Leukemia
Authors: Yoo Hong Min, June-Won Cheong, Mark Hong Lee, Ji Yeon Kim, Seung Tae Lee, Jee Sook Hahn, Yun Woong Ko
Journal: Clinical Cancer Research (2004)

Abstract Purpose: The F-box protein S-phase kinase-associated protein 2 (Skp2) positively regulates the G1-S phase transition by controlling the stability of several G1 regulators, such as p27Kip1. However, the clinical significance of Skp2 in patients with acute myelogenous leukemia (AML) remains unknown. Experimental Design: We examined the clinical and biological significance of Skp2 expression in AML and evaluated the relationship between Skp2 and p27Kip1 expression and phosphatase and tensin homologue (PTEN) phosphorylation. Results: Western blot analysis showed that high Skp2 expression was observed in 57 (57.6%) cases and significantly correlated with unfavorable cytogenetics (P = 0.035) but not with age, white blood cell count, serum lactic dehydrogenase level, and the French-American-British subtype. An inverse correlation was not observed between Skp2 and p27Kip1 expression. However, p27Kip1 protein was preferentially localized to cytoplasm in the high-Skp2-expression group. The cytoplasmic to nuclear ratio of p27Kip1 expression was significantly correlated with the levels of Skp2 expression (P &amp;lt; 0.001). The frequency of PTEN phosphorylation was significantly higher in the high-Skp2-expression group compared with the low- Skp2-expression group (P = 0.035). The Skp2 overexpression was significantly associated with shorter disease-free survival and overall survival (P = 0.0386 and P = 0.0369, respectively). Multivariate analysis showed that Skp2 expression was an independent prognostic factor both in the disease-free survival and overall survival. Conclusion: These findings suggest that Skp2 expression is an independent marker for a poor prognosis in AML. The presence of a positive correlation between Skp2 and phosphorylated PTEN suggests that an aberration in the PTEN/Skp2 signaling pathway might be operating in AML.
Psychosis as a State of Aberrant Salience: A Framework Linking Biology, Phenomenology, and Pharmacology in Schizophrenia
Authors: Shitij Kapur
Journal: American Journal of Psychiatry (2002)

OBJECTIVE: The clinical hallmark of schizophrenia is psychosis. The objective of this overview is to link the neurobiology (brain), the phenomenological experience (mind), and pharmacological aspects of psychosis-in-schizophrenia into a unitary framework. METHOD: Current ideas regarding the neurobiology and phenomenology of psychosis and schizophrenia, the role of dopamine, and the mechanism of action of antipsychotic medication were integrated to develop this framework. RESULTS: A central role of dopamine is to mediate the “salience” of environmental events and internal representations. It is proposed that a dysregulated, hyperdopaminergic state, at a “brain” level of description and analysis, leads to an aberrant assignment of salience to the elements of one’s experience, at a “mind” level. Delusions are a cognitive effort by the patient to make sense of these aberrantly salient experiences, whereas hallucinations reflect a direct experience of the aberrant salience of internal representations. Antipsychotics “dampen the salience” of these abnormal experiences and by doing so permit the resolution of symptoms. The antipsychotics do not erase the symptoms but provide the platform for a process of psychological resolution. However, if antipsychotic treatment is stopped, the dysregulated neurochemistry returns, the dormant ideas and experiences become reinvested with aberrant salience, and a relapse occurs. CONCLUSIONS: The article provides a heuristic framework for linking the psychological and biological in psychosis. Predictions of this hypothesis, particularly regarding the possibility of synergy between psychological and pharmacological therapies, are presented. The author describes how the hypothesis is complementary to other ideas about psychosis and also discusses its limitations.