tbuckley/cabot-search huggingface dataset:
Genome-wide copy number variation study associates metabotropic glutamate receptor gene networks with attention deficit hyperactivity disorder
Authors: Josephine Elia, Joseph T Glessner, Kai Wang, Nagahide Takahashi, Corina J Shtir, Dexter Hadley, Patrick M A Sleiman, Haitao Zhang, Cecilia E Kim, Reid Robison, Gholson J Lyon, James H Flory, Jonathan P Bradfield, Marcin Imielinski, Cuiping Hou, Edward C Frackelton, Rosetta M Chiavacci, Takeshi Sakurai, Cara Rabin, Frank A Middleton, Kelly A Thomas, Maria Garris, Frank Mentch, Christine M Freitag, Hans-Christoph Steinhausen, Alexandre A Todorov, Andreas Reif, Aribert Rothenberger, Barbara Franke, Eric O Mick, Herbert Roeyers, Jan Buitelaar, Klaus-Peter Lesch, Tobias Banaschewski, Richard P Ebstein, Fernando Mulas, Robert D Oades, Joseph Sergeant, Edmund Sonuga-Barke, Tobias J Renner, Marcel Romanos, Jasmin Romanos, Andreas Warnke, Susanne Walitza, Jobst Meyer, Haukur Pálmason, Christiane Seitz, Sandra K Loo, Susan L Smalley, Joseph Biederman, Lindsey Kent, Philip Asherson, Richard J L Anney, J William Gaynor, Philip Shaw, Marcella Devoto, Peter S White, Struan F A Grant, Joseph D Buxbaum, Judith L Rapoport, Nigel M Williams, Stanley F Nelson, Stephen V Faraone, Hakon Hakonarson
Journal: Nature Genetics (2011)
A phase I pharmacokinetic study of 21-day continuous infusion mitoxantrone.
Authors: J Greidanus, E G de Vries, N H Mulder, D T Sleijfer, D R Uges, B Oosterhuis, P H Willemse
Journal: Journal of Clinical Oncology (1989)

A phase I study of mitoxantrone given as a continuous infusion for 21 days using a venous access port and a portable pump was performed. The first dose step was 0.3 mg/m2/d for 21 days. Courses were repeated every 6 weeks. Dose increment per step was 0.1 mg/m2/d in the first three dose steps and 0.2 mg/m2/d in the latter dose steps. Twenty-five patients entered the study and received a total of 50 courses, with a median of two courses (range, one to five). Up to 0.5 mg/m2/d, no toxicity (according to the World Health Organization [WHO] criteria) occurred. At 0.7 mg/m2/d, one patient experienced grade 2 leukocytopenia and at the 0.9 mg/m2/d dose step, one patient experienced grade 2 leukocytopenia, grade 1 thrombocytopenia, and grade 1 hair loss. At 1.1 mg/m2/d, two of six patients had grade 3 leukocytopenia, and in one patient treatment was discontinued after two days because of myocardial infarction. In both patients receiving 1.3 mg/m2/d, treatment was discontinued after 2 weeks because of grade 3 leukocytopenia. Three patients at the 1.1 mg/m2/d, dose step and two patients at the 1.3 mg/m2/d dose step experienced some nausea in the last week of the infusion period. One patient developed subclavian vein thrombosis. No infectious complications occurred. Pharmacokinetic studies were performed by high-performance liquid chromatography (HPLC) with ultraviolet (UV) detection. Plasma steady-state was reached after 35 hours. During steady-state there was a linear relationship between the mitoxantrone dose administered and the level of mitoxantrone in plasma (r = .93, P less than .005). The mitoxantrone level in leukocytes increased significantly during the infusion period at the 0.9 mg/m2, the 1.1 mg/m2, and the 1.3 mg/m2 dose steps. The area under the curve (AUC) in leukocytes was higher with continuous infusion of 1.1 mg/m2/d for 21 days compared with bolus injection of 12 mg/m2. Mitoxantrone could be detected in plasma for at least five days after the end of the 21-day infusion period and in leukocytes for at least 14 days. Continuous infusion mitoxantrone may increase intracellular drug uptake as expressed by intracellular AUC. We recommend a dose of 1.1 mg/m2/d for 3 weeks for evaluation of antitumor efficacy in phase II studies.
Increased frequency of interleukin 2-responsive T cells specific for myelin basic protein and proteolipid protein in peripheral blood and cerebrospinal fluid of patients with multiple sclerosis.
Authors: J Zhang, S Markovic-Plese, B Lacet, J Raus, H L Weiner, D A Hafler
Journal: The Journal of Experimental Medicine (1994)

Equal numbers of CD4+ T cells recognizing myelin basic protein (MBP) and proteolipid protein (PLP) are found in the circulation of normal individuals and multiple sclerosis (MS) patients. We hypothesized that if myelin-reactive T cells are critical for the pathogenesis of MS, they would exist in a different state of activation as compared with myelin-reactive T cells cloned from the blood of normal individuals. This was investigated in a total of 62 subjects with definitive MS. While there were no differences in the frequencies of MBP- and PLP-reactive T cells after primary antigen stimulation, the frequency of MBP or PLP but not tetanus toxoid-reactive T cells generated after primary recombinant interleukin (rIL-2) stimulation was significantly higher in MS patients as compared with control individuals. Primary rIL-2-stimulated MBP-reactive T cell lines were CD4+ and recognized MBP epitopes 84-102 and 143-168 similar to MBP-reactive T cell lines generated with primary MBP stimulation. In the cerebrospinal fluid (CSF) of MS patients, MBP-reactive T cells generated with primary rIL-2 stimulation accounted for 7% of the IL-2-responsive cells, greater than 10-fold higher than paired blood samples, and these T cells also selectively recognized MBP peptides 84-102 and 143-168. In striking contrast, MBP-reactive T cells were not detected in CSF obtained from patients with other neurologic diseases. These results provide definitive in vitro evidence of an absolute difference in the activation state of myelin-reactive T cells in the central nervous system of patients with MS and provide evidence of a pathogenic role of autoreactive T cells in the disease.
Update of the Anopheles gambiae PEST genome assembly.
Authors: Maria V Sharakhova, Martin P Hammond, Neil F Lobo, Jaroslaw Krzywinski, Maria F Unger, Maureen E Hillenmeyer, Robert V Bruggner, Ewan Birney, Frank H Collins
Journal: Genome biology (2007)

Abstract Background The genome of Anopheles gambiae , the major vector of malaria, was sequenced and assembled in 2002. This initial genome assembly and analysis made available to the scientific community was complicated by the presence of assembly issues, such as scaffolds with no chromosomal location, no sequence data for the Y chromosome, haplotype polymorphisms resulting in two different genome assemblies in limited regions and contaminating bacterial DNA. Results Polytene chromosome in situ hybridization with cDNA clones was used to place 15 unmapped scaffolds (sizes totaling 5.34 Mbp) in the pericentromeric regions of the chromosomes and oriented a further 9 scaffolds. Additional analysis by in situ hybridization of bacterial artificial chromosome (BAC) clones placed 1.32 Mbp (5 scaffolds) in the physical gaps between scaffolds on euchromatic parts of the chromosomes. The Y chromosome sequence information (0.18 Mbp) remains highly incomplete and fragmented among 55 short scaffolds. Analysis of BAC end sequences showed that 22 inter-scaffold gaps were spanned by BAC clones. Unmapped scaffolds were also aligned to the chromosome assemblies in silico , identifying regions totaling 8.18 Mbp (144 scaffolds) that are probably represented in the genome project by two alternative assemblies. An additional 3.53 Mbp of alternative assembly was identified within mapped scaffolds. Scaffolds comprising 1.97 Mbp (679 small scaffolds) were identified as probably derived from contaminating bacterial DNA. In total, about 33% of previously unmapped sequences were placed on the chromosomes. Conclusion This study has used new approaches to improve the physical map and assembly of the A. gambiae genome.
Clarithromycin inhibits pandemic A/H1N1/2009 influenza virus infection in human airway epithelial cells
Authors: Mutsuo Yamaya, Yukimasa Hatachi, Hiroshi Kubo, Hidekazu Nishimura
Journal: European Respiratory Journal (2012)

Rationale:  We reported previously that clarithromycin (CAM), a macrolide antibiotic, inhibits seasonal type A influenza virus (H3N2) infection in human airways. However, the effects of CAM on infection by the pandemic A/H1N1/2009 influenza virus (A/H1 2009 pdm) have not been studied.   Methods:  Human tracheal epithelial cells (n=3) were pretreated with CAM (10 μM) and then infected with the A/H1 2009 pdm in 24-well plates.   Results:  The viral titer and the amount of interleukin (IL)-6, a pro-inflammatory cytokine, in the supernatant increased with time after A/H1 2009 pdm infection. CAM reduced the viral titer (6.7 ± 0.4 log TCID 50  units/ml/24 h for virus alone  vs.  4.9 ± 0.2 log TCID 50  units/ml/24 h for virus plus CAM; p vs.  149 ± 7 pg/ml/24 h for virus plus CAM; p 3 /well in virus alone  vs.  12 ± 2 x 10 3 /well in virus plus CAM; p 50  units/ml/24 h and 5 ± 1 x 10 3 /well for the A/H3N2 virus; p   Conclusion:  Clarithromycin may inhibit A/H1 2009 pdm infection and may modulate airway inflammation and epithelial damage during the infection. The A/H1 2009 pdm may release higher levels of virus and may be more cytotoxic than seasonal influenza virus (H3N2).
Repetitive Injections of Dendritic Cells Matured with Tumor Necrosis Factor α Induce Antigen-specific Protection of Mice from Autoimmunity
Authors: Mauritius Menges, Susanne Rößner, Constanze Voigtländer, Heike Schindler, Nicole A. Kukutsch, Christian Bogdan, Klaus Erb, Gerold Schuler, Manfred B. Lutz
Journal: The Journal of Experimental Medicine (2001)

Mature dendritic cells (DCs) are believed to induce T cell immunity, whereas immature DCs induce T cell tolerance. Here we describe that injections of DCs matured with tumor necrosis factor (TNF)-α (TNF/DCs) induce antigen-specific protection from experimental autoimmune encephalomyelitis (EAE) in mice. Maturation by TNF-α induced high levels of major histocompatibility complex class II and costimulatory molecules on DCs, but they remained weak producers of proinflammatory cytokines. One injection of such TNF/DCs pulsed with auto-antigenic peptide ameliorated the disease score of EAE. This could not be observed with immature DCs or DCs matured with lipopolysaccharide (LPS) plus anti-CD40. Three consecutive injections of peptide-pulsed TNF/DCs derived from wild-type led to the induction of peptide-specific predominantly interleukin (IL)-10–producing CD4+ T cells and complete protection from EAE. Blocking of IL-10 in vivo could only partially restore the susceptibility to EAE, suggesting an important but not exclusive role of IL-10 for EAE prevention. Notably, the protection was peptide specific, as TNF/DCs pulsed with unrelated peptide could not prevent EAE. In conclusion, this study describes that stimulation by TNF-α results in incompletely matured DCs (semi-mature DCs) which induce peptide-specific IL-10–producing T cells in vivo and prevent EAE.
Fetal Risk Associated With Rubella Vaccine
Authors: Stephen R. Preblud
Journal: JAMA (1981)

Ninety-four susceptible women received either Cendehill or HPV-77 rubella vaccine. All gave birth to healthy infants. Seventeen susceptible women received the RA 27/3 vaccine. All their infants were free of abnormalities compatible with congenital rubella, as were 54 born to mothers of unknown immune status at the time of RA 27/3 vaccination and those later found to be immune. An additional susceptible woman received an unknown strain of vaccine; she also had a healthy infant. The risk of severe congenital malformations after rubella vaccination is low. In our 112 cases, the maximum risk was approximately 3%. Concern about the potential adverse effects of rubella vaccine on the fetus should not interfere with vaccination of women of childbearing age. However, since the actual risk may not be zero, women known to be pregnant should not be vaccinated, and conception should be avoided for three months after vaccination.
New Gene Evolution in the Bonus-TIF1-γ/TRIM33 Family Impacted the Architecture of the Vertebrate Dorsal–Ventral Patterning Network
Authors: Robert G. Wisotzkey, Janine C. Quijano, Michael J. Stinchfield, Stuart J. Newfeld
Journal: Molecular Biology and Evolution (2014)

Uncovering how a new gene acquires its function and understanding how the function of a new gene influences existing genetic networks are important topics in evolutionary biology.Here, we demonstrate nonconservation for the embryonic functions of Drosophila Bonus and its newest vertebrate relative TIF1-c/TRIM33.We showed previously that TIF1-c/ TRIM33 functions as an ubiquitin ligase for the Smad4 signal transducer and antagonizes the Bone Morphogenetic Protein (BMP) signaling network underlying vertebrate dorsal-ventral axis formation.Here, we show that Bonus functions as an agonist of the Decapentaplegic (Dpp) signaling network underlying dorsal-ventral axis formation in flies.The absence of conservation for the roles of Bonus and TIF1-c/TRIM33 reveals a shift in the dorsal-ventral patterning networks of flies and mice, systems that were previously considered wholly conserved.The shift occurred when the new gene TIF1-c/TRIM33 replaced the function of the ubiquitin ligase Nedd4L in the lineage leading to vertebrates.Evidence of this replacement is our demonstration that Nedd4 performs the function of TIF1-c/TRIM33 in flies during dorsal-ventral axis formation.The replacement allowed vertebrate Nedd4L to acquire novel functions as a ubiquitin ligase of vertebrate-specific Smad proteins.Overall our data reveal that the architecture of the Dpp/BMP dorsal-ventral patterning network continued to evolve in the vertebrate lineage, after separation from flies, via the incorporation of new genes.
Effect of Protein Kinase Cβ Inhibition on Renal Hemodynamic Function and Urinary Biomarkers in Humans With Type 1 Diabetes: A Pilot Study
Authors: David Z.I. Cherney, Ana Konvalinka, Bernard Zinman, Eleftherios P. Diamandis, Anton Soosaipillai, Heather Reich, Joanne Lorraine, Vesta Lai, James W. Scholey, Judith A. Miller
Journal: Diabetes Care (2008)

The aim of this study was to examine the effect of protein kinase Cbeta inhibition with ruboxistaurin on renal hemodynamic function and urinary biomarkers (monocyte chemoattractant protein-1 [MCP-1] and epidermal growth factor) in renin angiotensin system blockade-treated type 1 diabetic subjects.Albuminuric subjects were randomized (2:1) to ruboxistaurin (32 mg daily; n = 13) or placebo (n = 7) for 8 weeks. Renal hemodynamic function was measured during clamped euglycemia or hyperglycemia and before and after ruboxistaurin or placebo.Ruboxistaurin was not associated with between-group differences during clamped euglycemia or hyperglycemia. In a post hoc analysis comparing hyperfilterers with normofilterers during euglycemia, glomerular filtration rate and MCP-1 decreased, whereas the epidermal growth factor-to-MCP-1 ratio increased in hyperfilterers versus normofilterers (all P < 0.05).The effect of ruboxistaurin is modest and dependent, at least in part, on the level of ambient glycemia and baseline glomerular filtration rate.
Patterns and distribution of tobacco consumption in India: cross sectional multilevel evidence from the 1998-9 national family health survey
Authors: S V Subramanian, Shailen Nandy, Michelle Kelly, Dave Gordon, George Davey Smith
Journal: BMJ (2004)

To investigate the demographic, socioeconomic, and geographical distribution of tobacco consumption in India.Multilevel cross sectional analysis of the 1998-9 Indian national family health survey of 301 984 individuals in 92 447 households in 3215 villages in 440 districts in 26 states.Indian states.301 984 adults (> or = 18 years).Dichotomous variable for smoking and chewing tobacco for each respondent (1 if yes, 0 if no) as well as a combined measure of whether an individual smokes, chews tobacco, or both.Smoking and chewing tobacco are systematically associated with socioeconomic markers at the individual and household level. Individuals with no education are 2.69 times more likely to smoke and chew tobacco than those with postgraduate education. Households belonging to the lowest fifth of a standard of living index were 2.54 times more likely to consume tobacco than those in the highest fifth. Scheduled tribes (odds ratio 1.23, 95% confidence interval 1.18 to 1.29) and scheduled castes (1.19, 1.16 to 1.23) were more likely to consume tobacco than other caste groups. The socioeconomic differences are more marked for smoking than for chewing tobacco. Socioeconomic markers and demographic characteristics of individuals and households do not account fully for the differences at the level of state, district, and village in smoking and chewing tobacco, with state accounting for the bulk of the variation in tobacco consumption.The distribution of tobacco consumption is likely to maintain, and perhaps increase, the current considerable socioeconomic differentials in health in India. Interventions aimed at influencing change in tobacco consumption should consider the socioeconomic and geographical determinants of people's susceptibility to consume tobacco.
Does iron overload really matter in stem cell transplantation?
Authors: Philippe Armand, Marie‐Michele Sainvil, Haesook T. Kim, Joanna Rhodes, Corey Cutler, Vincent T. Ho, John Koreth, Edwin P. Alyea, Ellis J. Neufeld, Raymond Y. Kwong, Robert J. Soiffer, Joseph H. Antin
Journal: American Journal of Hematology (2012)

A growing body of evidence suggests that iron overload is associated with inferior outcomes after myeloablative allogeneic hematopoietic stem cell transplantation (HSCT). However, all of those studies used surrogate markers of iron overload, especially serum ferritin, and most had a retrospective design. We conducted a prospective observational study in patients with myelodysplastic syndrome or acute leukemia undergoing myeloablative HSCT. Forty-five patients who were followed for over 1 year, with serial measurements of serum iron parameters, as well as liver and cardiac magnetic resonance imaging. There was no significant increase in ferritin, liver or cardiac iron content in the 12 months following HSCT. Although serum ferritin still appeared to have prognostic significance, as previously reported, pre-HSCT iron overload (as reflected in liver iron content) was not associated with increased mortality, relapse, or graft-versus-host disease. These results raise the possibility that the adverse prognostic impact of pre-HSCT hyperferritinemia may be related to factors independent of iron overload.
Detection of C3d-Binding Donor-Specific Anti-HLA Antibodies at Diagnosis of Humoral Rejection Predicts Renal Graft Loss
Authors: Antoine Sicard, Stéphanie Ducreux, Maud Rabeyrin, Lionel Couzi, Brigitte McGregor, Lionel Badet, Jean Yves Scoazec, Thomas Bachelet, Sébastien Lepreux, Jonathan Visentin, Pierre Merville, Véronique Fremeaux-Bacchi, Emmanuel Morelon, Jean-Luc Taupin, Valérie Dubois, Olivier Thaunat
Journal: Journal of the American Society of Nephrology (2014)

Antibody-mediated rejection (AMR) is a major cause of kidney graft loss, yet assessment of individual risk at diagnosis is impeded by the lack of a reliable prognosis assay. Here, we tested whether the capacity of anti-HLA antibodies to bind complement components allows accurate risk stratification at the time of AMR diagnosis. Among 938 kidney transplant recipients for whom a graft biopsy was performed between 2004 and 2012 at the Lyon University Hospitals, 69 fulfilled the diagnosis criteria for AMR and were enrolled. Sera banked at the time of the biopsy were screened for the presence of donor-specific anti-HLA antibodies (DSAs) and their ability to bind C1q and C3d using flow bead assays. In contrast with C4d graft deposition, the presence of C3d-binding DSA was associated with a higher risk of graft loss (P<0.001). Despite similar trend, the difference did not reach significance with a C1q-binding assay (P=0.06). The prognostic value of a C3d-binding assay was further confirmed in an independent cohort of 39 patients with AMR (P=0.04). Patients with C3d-binding antibodies had worse eGFR and higher DSA mean fluorescence intensity. In a multivariate analysis, only eGFR <30 ml/min per 1.73 m(2) (hazard ratio [HR], 3.56; 95% confidence interval [CI], 1.46 to 8.70; P=0.005) and the presence of circulating C3d-binding DSA (HR, 2.80; 95% CI, 1.12 to 6.95; P=0.03) were independent predictors for allograft loss at AMR diagnosis. We conclude that assessment of the C3d-binding capacity of DSA at the time of AMR diagnosis allows for identification of patients at risk for allograft loss.
Apoptotic resistance to ionizing radiation in pediatric B-precursor acute lymphoblastic leukemia frequently involves increased NF-κB survival pathway signaling
Authors: Victoria J. Weston, Belinda Austen, Wenbin Wei, Eliot Marston, Azra Alvi, Sarah Lawson, Philip J. Darbyshire, Mike Griffiths, Frank Hill, Jill R. Mann, Paul A. H. Moss, A. Malcolm R. Taylor, Tatjana Stankovic
Journal: Blood (2004)
Lithocholic acid disrupts phospholipid and sphingolipid homeostasis leading to cholestasis in mice
Authors: Tsutomu Matsubara, Naoki Tanaka, Andrew D. Patterson, Joo-Youn Cho, Kristopher W. Krausz, Frank J. Gonzalez
Journal: Hepatology (2011)

Lithocholic acid (LCA) is an endogenous compound associated with hepatic toxicity during cholestasis. LCA exposure in mice resulted in decreased serum lysophosphatidylcholine (LPC) and sphingomyelin levels due to elevated lysophosphatidylcholine acyltransferase (LPCAT) and sphingomyelin phosphodiesterase (SMPD) expression. Global metabolome analysis indicated significant decreases in serum palmitoyl-, stearoyl-, oleoyl-, and linoleoyl-LPC levels after LCA exposure. LCA treatment also resulted in decreased serum sphingomyelin levels and increased hepatic ceramide levels, and induction of LPCAT and SMPD messenger RNAs (mRNAs). Transforming growth factor-β (TGF-β) induced Lpcat2/4 and Smpd3 gene expression in primary hepatocytes and the induction was diminished by pretreatment with the SMAD3 inhibitor SIS3. Furthermore, alteration of the LPCs and Lpcat1/2/4 and Smpd3 expression was attenuated in LCA-treated farnesoid X receptor-null mice that are resistant to LCA-induced intrahepatic cholestasis. Conclusion: This study revealed that LCA induced disruption of phospholipid/sphingolipid homeostasis through TGF-β signaling and that serum LPC is a biomarker for biliary injury. (HEPATOLOGY 2011;)