tbuckley/cabot-search huggingface dataset:
Increased Fluorine-18 2-Fluoro-2-Deoxy-D-Glucose (FDG) Uptake in Childhood CNS Tumors Is Correlated With Malignancy Grade: A Study With FDG Positron Emission Tomography/Magnetic Resonance Imaging Coregistration and Image Fusion
Authors: Lise Borgwardt, Liselotte Højgaard, Henrik Carstensen, Henning Laursen, Markus Nowak, Carsten Thomsen, Kjeld Schmiegelow
Journal: Journal of Clinical Oncology (2005)

PURPOSE Positron emission tomography (PET) has been used in grading of CNS tumors in adults, whereas studies of children have been limited. PATIENTS AND METHODS Nineteen boys and 19 girls (median age, 8 years) with primary CNS tumors were studied prospectively by fluorine-18 2-fluoro-2-deoxy-D-glucose (FDG) PET with (n = 16) or without (n = 22) H(2)(15)O-PET before therapy. Image processing included coregistration to magnetic resonance imaging (MRI) in all patients. The FDG uptake in tumors was semiquantitatively calculated by a region-of-interest-based tumor hotspot/brain index. Eight tumors without histologic confirmation were classified as WHO grade 1 based on location, MRI, and clinical course (22 to 42 months). Results Four grade 4 tumors had a mean index of 4.27 +/- 0.5, four grade 3 tumors had a mean index of 2.47 +/- 1.07, 10 grade 2 tumors had a mean index of 1.34 +/- 0.73, and eight of 12 grade 1 tumors had a mean index of -0.31 +/- 0.59. Eight patients with no histologic confirmation had a mean index of 1.04. For these 34 tumors, FDG uptake was positively correlated with malignancy grading (n = 34; r = 0.72; P < .01), as for the 26 histologically classified tumors (n = 26; r = 0.89; P < .01). The choroid plexus papilloma (n = 1) and the pilocytic astrocytomas (n = 3) had a mean index of 3.26 (n = 38; r = 0.57; P < .01). H(2)(15)O-uptake showed no correlation with malignancy. Digitally performed PET/MRI coregistration increased information on tumor characterization in 90% of cases. CONCLUSION FDG PET of the brain with MRI coregistration can be used to obtain a more specific diagnosis with respect to malignancy grading. Improved PET/MRI imaging of the benign hypermetabolic tumors is needed to optimize clinical use.
HSC70 blockade by the therapeutic peptide P140 affects autophagic processes and endogenous MHCII presentation in murine lupus
Authors: N. Page, F. Gros, N. Schall, M. Decossas, D. Bagnard, J.-P. Briand, S. Muller
Journal: Annals of the Rheumatic Diseases (2010)

<h3>Background</h3> The P140 phosphopeptide issued from the spliceosomal U1-70K small nuclear ribonucleoprotein protein displays protective properties in MRL/lpr lupus-prone mice. It binds both major histocompatibility class II (MHCII) and HSC70/Hsp73 molecules. P140 peptide increases MRL/lpr peripheral blood lymphocyte apoptosis and decreases autoepitope recognition by T cells. <h3>Objective</h3> To explore further the mode of action of P140 peptide on HSC70+ antigen-presenting cells. <h3>Methods</h3> P140 biodistribution was monitored in real time using an imaging system and by fluorescence and electron microscopy. Fluorescence activated cell sorting and Western blotting experiments were used to evaluate the P140 effects on autophagic flux markers. <h3>Results</h3> P140 fluorescence accumulated especially in the lungs and spleen. P140 peptide reduced the number of peripheral and splenic T and B cells without affecting these cells in normal mice. Remaining MRL/lpr B cells responded normally to mitogens. P140 peptide decreased the expression levels of HSC70/Hsp73 chaperone and stable MHCII dimers, which are both increased in MRL/lpr splenic B cells. It impaired refolding properties of chaperone HSC70. In MRL/lpr B cells, it increased the accumulation of the autophagy markers p62/SQSTM1 and LC3-II, consistent with a downregulated lysosomal degradation during autophagic flux. <h3>Conclusion</h3> The study results suggest that after P140 peptide binding to HSC70, the endogenous (auto)antigen processing might be greatly affected in MRL/lpr antigen-presenting B cells, leading to the observed decrease of autoreactive T-cell priming and signalling via a mechanism involving a lysosomal degradation pathway. This unexpected mechanism might explain the beneficial effect of P140 peptide in treated MRL/lpr mice.
Role of <i>BMPR2</i> Alternative Splicing in Heritable Pulmonary Arterial Hypertension Penetrance
Authors: Joy Cogan, Eric Austin, Lora Hedges, Bethany Womack, James West, James Loyd, Rizwan Hamid
Journal: Circulation (2012)

Bone morphogenic protein receptor 2 (BMPR2) gene mutations are the most common cause of heritable pulmonary arterial hypertension. However, only 20% of mutation carriers get clinical disease. Here, we explored the hypothesis that this reduced penetrance is due in part to an alteration in BMPR2 alternative splicing.Our data showed that BMPR2 has multiple alternative spliced variants. Two of these, isoform-A (full length) and isoform-B (missing exon 12), were expressed in all tissues analyzed. Analysis of cultured lymphocytes of 47 BMPR2 mutation-positive heritable pulmonary arterial hypertension patients and 35 BMPR2 mutation-positive unaffected carriers showed that patients had higher levels of isoform-B compared with isoform-A (B/A ratio) than carriers (P=0.002). Furthermore, compared with cells with a low B/A ratio, cells with a high B/A ratio had lower levels of unphosphorylated cofilin after BMP stimulation. Analysis of exon 12 sequences identified an exonic splice enhancer that binds serine arginine splicing factor 2 (SRSF2). Because SRSF2 promotes exon inclusion, reduced SRSF2 expression would mean that exon 12 would not be included in final BMPR2 mRNA (thus promoting increased isoform-B formation). Western blot analysis showed that SRSF2 expression was lower in cells from patients compared with cells from carriers and that siRNA-mediated knockdown of SRSF2 in pulmonary microvascular endothelial cells resulted in elevated levels of isoform-B compared with isoform-A, ie, an elevated B/A ratio.Alterations in BMPR2 isoform ratios may provide an explanation of the reduced penetrance among BMPR2 mutation carriers. This ratio is controlled by an exonic splice enhancer in exon 12 and its associated splicing factor, SRSF2.
Dysregulation of voltage-gated sodium channels by ubiquitin ligase NEDD4-2 in neuropathic pain
Authors: Cédric J. Laedermann, Matthieu Cachemaille, Guylène Kirschmann, Marie Pertin, Romain-Daniel Gosselin, Isabelle Chang, Maxime Albesa, Chris Towne, Bernard L. Schneider, Stephan Kellenberger, Hugues Abriel, Isabelle Decosterd
Journal: Journal of Clinical Investigation (2013)

Peripheral neuropathic pain is a disabling condition resulting from nerve injury. It is characterized by the dysregulation of voltage-gated sodium channels (Navs) expressed in dorsal root ganglion (DRG) sensory neurons. The mechanisms underlying the altered expression of Na(v)s remain unknown. This study investigated the role of the E3 ubiquitin ligase NEDD4-2, which is known to ubiquitylate Navs, in the pathogenesis of neuropathic pain in mice. The spared nerve injury (SNI) model of traumatic nerve injury-induced neuropathic pain was used, and an Na(v)1.7-specific inhibitor, ProTxII, allowed the isolation of Na(v)1.7-mediated currents. SNI decreased NEDD4-2 expression in DRG cells and increased the amplitude of Na(v)1.7 and Na(v)1.8 currents. The redistribution of Na(v)1.7 channels toward peripheral axons was also observed. Similar changes were observed in the nociceptive DRG neurons of Nedd4L knockout mice (SNS-Nedd4L(-/-)). SNS-Nedd4L(-/-) mice exhibited thermal hypersensitivity and an enhanced second pain phase after formalin injection. Restoration of NEDD4-2 expression in DRG neurons using recombinant adenoassociated virus (rAAV2/6) not only reduced Na(v)1.7 and Na(v)1.8 current amplitudes, but also alleviated SNI-induced mechanical allodynia. These findings demonstrate that NEDD4-2 is a potent posttranslational regulator of Na(v)s and that downregulation of NEDD4-2 leads to the hyperexcitability of DRG neurons and contributes to the genesis of pathological pain.
A Single siRNA Suppresses Fatal Encephalitis Induced by Two Different Flaviviruses
Authors: Priti Kumar, Sang Kyung Lee, Premlata Shankar, N Manjunath
Journal: PLoS Medicine (2006)

Background Japanese encephalitis virus (JEV) and West Nile virus (WNV) are neurotropic flaviviruses that can cause acute encephalitis with a high fatality rate. Currently there is no effective treatment for these infections. Methods and Findings We tested RNA interference (RNAi)-based intervention to suppress lethal JE and WN encephalitis in mice. To induce RNAi, we used either lentivirally expressed short hairpin RNA (shRNA) or synthetic short interfering RNA (siRNA). As target, we selected the cd loop-coding sequence in domain II of the viral Envelope protein, which is highly conserved among all flaviviruses because of its essential role in membrane fusion. Using as a target a species-specific sequence in the cd loop that is conserved only among the different strains of either JEV or WNV, we could achieve specific protection against the corresponding virus. However, by targeting a cross-species conserved sequence within the cd loop, we were able to protect mice against encephalitis induced by both viruses. A single intracranial administration of lentivirally delivered shRNA or lipid-complexed siRNA before viral challenge or siRNA treatment after viral challenge was sufficient for protection against lethal encephalitis. Conclusions RNAi-based intervention affords near complete protection from both JEV- and WNV- induced encephalitis in mice. Our results show, to our knowledge for the first time, that siRNA can be used as a broad-spectrum antiviral agent for treating encephalitis caused by multiple related viruses.
Differences in the dynamics of parathyroid hormone secretion in hemodialysis patients with marked secondary hyperparathyroidism.
Authors: A J Felsenfeld, A Jara, M Pahl, J Bover, M Rodriguez
Journal: Journal of the American Society of Nephrology (1995)

Hemodialysis patients with predialysis intact parathyroid hormone (PTH) levels of more than 500 pg/mL are generally considered to have marked secondary hyperparathyroidism. Because the serum calcium level in these patients varies from low to high, it is not clear whether every hemodialysis patient with a PTH level > 500 pg/mL is part of a uniform group. The dynamics of PTH secretion in 21 hemodialysis patients with predialysis (basal) intact PTH levels > 500 pg/mL (range, 506 to 1978 pg/mL) has been evaluated. The basal/maximal PTH ratio, an indicator of the degree of relative PTH stimulation in the baseline state, was inversely correlated with the maximal PTH (r = -0.71), the basal serum calcium (r = -0.70), and the difference between the serum calcium at basal and maximal PTH (r = 0.81); the latter is the decrement in serum calcium from baseline necessary to maximally stimulate PTH. Because the basal PTH level appeared to be disproportionately influenced by hypocalcemia, the 21 patients were separated into two groups on the basis of the basal serum calcium (Group I < 9 mg/dL and Group II > 9 mg/dL). Basal PTH was not different between the two groups, even though maximally stimulated PTH (1,219 +/- 204 versus 2,739 +/- 412 pg/mL; P < 0.01) as induced by hypocalcemia and maximally suppressed PTH (217 +/- 37 versus 528 +/- 104; P = 0.05) as induced by hypercalcemia were less in Group I with the low basal calcium; moreover, the ratio of basal/maximal PTH was higher (73 +/- 6 versus 47 +/- 5%; P < 0.01) in Group I with the low basal calcium. These results suggest that the reason for a basal PTH > 500 pg/mL may be different among hemodialysis patients. In hypocalcemic patients, the low serum calcium appeared to be a major impetus for the high basal PTH level. In conclusion, (1) the maximally stimulated PTH appears to provide a better means of separating patients with marked secondary hyperparathyroidism than the basal PTH and (2) hemodialysis patients with basal PTH levels > 500 pg/mL may not be a uniform group.
Improving Relative Survival, But Large Remaining Differences in Survival for Non-Hodgkin's Lymphoma Across Europe and the United States From 1990 to 2004
Authors: Saskia A.M. van de Schans, Adam Gondos, Dick Johan van Spronsen, Jadwiga Rachtan, Bernd Holleczek, Roberto Zanetti, Jan Willem W. Coebergh, Maryska L.G. Janssen-Heijnen, Hermann Brenner
Journal: Journal of Clinical Oncology (2010)

Purpose Non-Hodgkin's lymphoma (NHL) is the most common hematologic malignant neoplasm in adults. Monitoring differential changes in population-based survival is across Europe and the United States (US) could point to progress attained and impact of application of novel treatments. Patients and Methods We examined trends in age-specific 5-year relative survival among patients with NHL age 15 years or older between 1990 and 1994 and 2000 and 2004, on the basis of follow-up data from 12 population-based cancer registries across Europe, using period analysis techniques and compared the results with similar trends of patients with NHL in the US, as recorded in the Surveillance, Epidemiology, and End Results database. Results By 2000 to 2004, overall 5-year relative survival of patients with NHL across Europe was between 37% and 62%, achieved by overall increases in 5-year relative survival ranging from 4% to 12% units between 1990 and 1994 and 2000 and 2004. Changes in age-specific survival ranged from −1% to 43% units during the same time interval. For patients with NHL older than age 55 years, relative survival in individual European registries for the whole period was between 8% and 36% units lower than in the US, theoretically representing a lag of 4 to 10 years of progress. Conclusion Our analyses disclosed a strong and ongoing increase in long-term survival for patients with NHL in European populations. The geographic differences potentially indicate that further improvements could be possible, especially for patients age 55 years or older. The presumptive delay in improvement in survival among elderly patients with NHL in Europe remains to be clarified.
Gene Transfer of Endothelial Nitric Oxide Synthase to the Lung of the Mouse In Vivo
Authors: Hunter C. Champion, Trinity J. Bivalacqua, Fiona M. D’Souza, Luis A. Ortiz, James R. Jeter, Kazunori Toyoda, Donald D. Heistad, Albert L. Hyman, Philip J. Kadowitz
Journal: Circulation Research (1999)

The effects of transfer of the endothelial nitric oxide synthase (eNOS) gene to the lung were studied in mice. After intratracheal administration of AdCMVbetagal, expression of the beta-galactosidase reporter gene was detected in pulmonary airway cells, in alveolar cells, and in small pulmonary arteries. Gene expression with AdCMVbetagal peaked 1 day after administration and decayed over a 7- to 14-day period, whereas gene expression after AdRSVbetagal transfection peaked on day 5 and was sustained over a 21- to 28-day period. One day after administration of AdCMVeNOS, eNOS protein levels were increased, and there was a small reduction in mean pulmonary arterial pressure and pulmonary vascular resistance. The pressure-flow relationship in the pulmonary vascular bed was shifted to the right in animals transfected with eNOS, and pulmonary vasodepressor responses to bradykinin and the type V cGMP-selective phosphodiesterase inhibitor zaprinast were enhanced, whereas systemic responses were not altered. Pulmonary vasopressor responses to endothelin-1 (ET-1), angiotensin II, and ventilatory hypoxia were reduced significantly in animals transfected with the eNOS gene, whereas pressor responses to norepinephrine and U46619 were not changed. Systemic pressor responses to ET-1 and angiotensin II were similar in eNOS-transfected mice and in control mice. Intratracheal administration of AdRSVeNOS attenuated the increase in pulmonary arterial pressure in mice exposed to the fibrogenic anticancer agent bleomycin. These data suggest that transfer of the eNOS gene in vivo can selectively reduce pulmonary vascular resistance and pulmonary pressor responses to ET-1, angiotensin II, and hypoxia; enhance pulmonary depressor responses; and attenuate pulmonary hypertension induced by bleomycin. Moreover, these data suggest that in vivo gene transfer may be a useful therapeutic intervention for the treatment of pulmonary hypertensive disorders.
Long-term toxicity of holmium-loaded poly(l-lactic acid) microspheres in rats
Authors: Sander W. Zielhuis, J. Frank W. Nijsen, Jan-Henry Seppenwoolde, Chris J.G. Bakker, Gerard C. Krijger, Hub F.J. Dullens, Bernard A. Zonnenberg, Peter P. van Rijk, Wim E. Hennink, Alfred D. van het Schip
Journal: Biomaterials (2007)
Prevalence of HPV Infection Among Females in the United States
Authors: Eileen F. Dunne, Elizabeth R. Unger, Maya Sternberg, Geraldine McQuillan, David C. Swan, Sonya S. Patel, Lauri E. Markowitz
Journal: JAMA (2007)

Human papillomavirus (HPV) infection is estimated to be the most common sexually transmitted infection. Baseline population prevalence data for HPV infection in the United States before widespread availability of a prophylactic HPV vaccine would be useful.To determine the prevalence of HPV among females in the United States.The National Health and Nutrition Examination Survey (NHANES) uses a representative sample of the US noninstitutionalized civilian population. Females aged 14 to 59 years who were interviewed at home for NHANES 2003-2004 were examined in a mobile examination center and provided a self-collected vaginal swab specimen. Swabs were analyzed for HPV DNA by L1 consensus polymerase chain reaction followed by type-specific hybridization. Demographic and sexual behavior information was obtained from all participants.HPV prevalence by polymerase chain reaction.The overall HPV prevalence was 26.8% (95% confidence interval [CI], 23.3%-30.9%) among US females aged 14 to 59 years (n = 1921). HPV prevalence was 24.5% (95% CI, 19.6%-30.5%) among females aged 14 to 19 years, 44.8% (95% CI, 36.3%-55.3%) among women aged 20 to 24 years, 27.4% (95% CI, 21.9%-34.2%) among women aged 25 to 29 years, 27.5% (95% CI, 20.8%-36.4%) among women aged 30 to 39 years, 25.2% (95% CI, 19.7%-32.2%) among women aged 40 to 49 years, and 19.6% (95% CI, 14.3%-26.8%) among women aged 50 to 59 years. There was a statistically significant trend for increasing HPV prevalence with each year of age from 14 to 24 years (P<.001), followed by a gradual decline in prevalence through 59 years (P = .06). HPV vaccine types 6 and 11 (low-risk types) and 16 and 18 (high-risk types) were detected in 3.4% of female participants; HPV-6 was detected in 1.3% (95% CI, 0.8%-2.3%), HPV-11 in 0.1% (95% CI, 0.03%-0.3%), HPV-16 in 1.5% (95% CI, 0.9%-2.6%), and HPV-18 in 0.8% (95% CI, 0.4%-1.5%) of female participants. Independent risk factors for HPV detection were age, marital status, and increasing numbers of lifetime and recent sex partners.HPV is common among females in the United States. Our data indicate that the burden of prevalent HPV infection among females was greater than previous estimates and was highest among those aged 20 to 24 years. However, the prevalence of HPV vaccine types was relatively low.
Bone Density in Breast Cancer: When to Intervene?
Authors: Julie R. Gralow
Journal: Journal of Clinical Oncology (2007)

The increased fracture risk associated with treatment-related loss of bone mineral density is an increasingly important problem for women diagnosed with breast cancer. In premenopausal patients, chemotherapy-induced ovarian failure and adjuvant ovarian suppression/ablation can lead to rapid and profound loss of bone mineral density. 1 In addition, in contrast to its bone mineral density–preserving effects seen in the postmenopausal setting, tamoxifen is associated with decreases in bone mineral density in premenopausal women. 2,3 In postmenopausal patients, the progressive loss of bone density associated with natural ovarian failure and aging, and the increasingly common use of adjuvant aromatase inhibition, which exacerbates the estrogen deprivation state, contribute to increased osteoporosis and fracture rates. In recognition of the increasing impact of cancer treatment on our patients’ bone health, the 2003 American Society of Clinical Oncology (ASCO) clinical practice guideline panel on bisphosphonates and bone health in women with breast cancer stated strongly that “oncology professionals, especially medical oncologists, need to take an expanded role in the routine and regular assessment of osteoporosis risk in women with breast cancer.” 4
Statins and Ischemic Stroke
Authors: J. David Spence
Journal: JAMA (2014)

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Accuracy of Electronically Reported “Meaningful Use” Clinical Quality Measures
Authors: Lisa M. Kern, Sameer Malhotra, Yolanda Barrón, Jill Quaresimo, Rina Dhopeshwarkar, Michelle Pichardo, Alison M. Edwards, Rainu Kaushal
Journal: Annals of Internal Medicine (2013)

Chinese translation Background: The federal Electronic Health Record Incentive Program requires electronic reporting of quality from electronic health records, beginning in 2014. Whether electronic reports of quality are accurate is unclear. Objective: To measure the accuracy of electronic reporting compared with manual review. Design: Cross-sectional study. Setting: A federally qualified health center with a commercially available electronic health record. Patients: All adult patients eligible in 2008 for 12 quality measures (using 8 unique denominators) were identified electronically. One hundred fifty patients were randomly sampled per denominator, yielding 1154 unique patients. Measurements: Receipt of recommended care, assessed by both electronic reporting and manual review. Sensitivity, specificity, positive and negative predictive values, positive and negative likelihood ratios, and absolute rates of recommended care were measured. Results: Sensitivity of electronic reporting ranged from 46% to 98% per measure. Specificity ranged from 62% to 97%, positive predictive value from 57% to 97%, and negative predictive value from 32% to 99%. Positive likelihood ratios ranged from 2.34 to 24.25 and negative likelihood ratios from 0.02 to 0.61. Differences between electronic reporting and manual review were statistically significant for 3 measures: Electronic reporting underestimated the absolute rate of recommended care for 2 measures (appropriate asthma medication [38% vs. 77%; P < 0.001] and pneumococcal vaccination [27% vs. 48%; P < 0.001]) and overestimated care for 1 measure (cholesterol control in patients with diabetes [57% vs. 37%; P = 0.001]). Limitation: This study addresses the accuracy of the measure numerator only. Conclusion: Wide measure-by-measure variation in accuracy threatens the validity of electronic reporting. If variation is not addressed, financial incentives intended to reward high quality may not be given to the highest-quality providers. Primary Funding Source: Agency for Healthcare Research and Quality.