bluuebunny/crossref_metadata_2025_split huggingface dataset:
Heterogeneous in vitro effects of doxorubicin on gene expression in primary human liposarcoma cultures
Authors: Daigeler Adrien , Klein-Hitpass Ludger , Chromik Ansgar Michael , Müller Oliver , Hauser Jörg , Homann Heinz-Herbert , Steinau Hans-Ulrich , Lehnhardt Marcus 
Published: October 2008

Abstract

Background
Doxorubicin is considered one of the most potent established chemotherapeutics in the treatment of liposarcoma; however, the response rates usually below 30%, are still disappointing. This study was performed to identify gene expression changes in liposarcoma after doxorubicin treatment.

Methods
Cells of 19 primary human liposarcoma were harvested intraoperatively and brought into cell culture. Cells were incubated with doxorubicin for 24 h, RNA was isolated and differential gene expression was analysed by the microarray technique.

Results
A variety of genes involved in apoptosis were up and down regulated in different samples revealing a heterogeneous expression pattern of the 19 primary tumor cell cultures in response to doxorubicin treatment. However, more than 50% of the samples showed up-regulation of pro-apoptotic genes such as TRAIL Receptor2, CDKN1A, GADD45A, FAS, CD40, PAWR, NFKBIA, IER3, PSEN1, RIPK2, and CD44. The anti-apoptotic genes TNFAIP3, PEA15, Bcl2A1, NGFB, and BIRC3 were also up-regulated. The pro-apoptotic CD14, TIA1, and ITGB2 were down-regulated in more than 50% of the tumor cultures after treatment with doxorubicin, as was the antiapoptotic YWHAH.

Conclusion
Despite a correlation of the number of differentially regulated genes to the tumor grading and to a lesser extent histological subtype, the expression patterns varied strongly; however, especially among high grade tumors the responses of selected apoptosis genes were similar. The predescribed low clinical response rates of low grade liposarcoma to doxorubicin correspond to our results with only little changes on gene expression level and also divergent findings concerning the up- and down-regulation of single genes in the different sarcoma samples.
A general SNP-based molecular barcode for Plasmodium falciparum identification and tracking
Authors: Daniels Rachel , Volkman Sarah K , Milner Danny A , Mahesh Nira , Neafsey Daniel E , Park Daniel J , Rosen David , Angelino Elaine , Sabeti Pardis C , Wirth Dyann F , Wiegand Roger C 
Published: October 2008

Abstract

Background
Single nucleotide polymorphism (SNP) genotyping provides the means to develop a practical, rapid, inexpensive assay that will uniquely identify any Plasmodium falciparum parasite using a small amount of DNA. Such an assay could be used to distinguish recrudescence from re-infection in drug trials, to monitor the frequency and distribution of specific parasites in a patient population undergoing drug treatment or vaccine challenge, or for tracking samples and determining purity of isolates in the laboratory during culture adaptation and sub-cloning, as well as routine passage.

Methods
A panel of twenty-four SNP markers has been identified that exhibit a high minor allele frequency (average MAF > 35%), for which robust TaqMan genotyping assays were constructed. All SNPs were identified through whole genome sequencing and MAF was estimated through Affymetrix array-based genotyping of a worldwide collection of parasites. These assays create a "molecular barcode" to uniquely identify a parasite genome.

Results
Using 24 such markers no two parasites known to be of independent origin have yet been found to have the same allele signature. The TaqMan genotyping assays can be performed on a variety of samples including cultured parasites, frozen whole blood, or whole blood spotted onto filter paper with a success rate > 99%. Less than 5 ng of parasite DNA is needed to complete a panel of 24 markers. The ability of this SNP panel to detect and identify parasites was compared to the standard molecular methods, MSP-1 and MSP-2 typing.

Conclusion
This work provides a facile field-deployable genotyping tool that can be used without special skills with standard lab equipment, and at reasonable cost that will unambiguously identify and track P. falciparum parasites both from patient samples and in the laboratory.
Development of selective blockers for Ca2+-activated Cl- channel using Xenopus laevis oocytes with an improved drug screening strategy
Authors: Oh Soo-Jin , Park Jung Hwan , Han Sungyu , Lee Jae Kyun , Roh Eun Joo , Lee C Justin 
Published: October 2008

AbstractBackgroundCa2+-activated Cl-channels (CaCCs) participate in many important physiological processes. However, the lack of effective and selective blockers has hindered the study of these channels, mostly due to the lack of good assay system. Here, we have developed a reliable drug screening method for better blockers of CaCCs, using the endogeneous CaCCs inXenopus laevisoocytes and two-electrode voltage-clamp (TEVC) technique.ResultsOocytes were prepared with a treatment of Ca2+ionophore, which was followed by a treatment of thapsigargin which depletes Ca2+stores to eliminate any contribution of Ca2+release. TEVC was performed with micropipette containing chelerythrine to prevent PKC dependent run-up or run-down. Under these conditions, Ca2+-activated Cl-currents induced by bath application of Ca2+to oocytes showed stable peak amplitude when repetitively activated, allowing us to test several concentrations of a test compound from one oocyte. Inhibitory activities of commercially available blockers and synthesized anthranilic acid derivatives were tested using this method. As a result, newly synthesizedN-(4-trifluoromethylphenyl)anthranilic acid with trifluoromethyl group (-CF3) atparaposition on the benzene ring showed the lowest IC50.ConclusionOur results provide an optimal drug screening strategy suitable for high throughput screening, and proposeN-(4-trifluoromethylphenyl)anthranilic acid as an improved CaCC blocker.
Changes in protein expression during honey bee larval development
Authors: Chan Queenie WT , Foster Leonard J 
Published: October 2008

Abstract
Background
The honey bee (Apis mellifera), besides its role in pollination and honey production, serves as a model for studying the biochemistry of development, metabolism, and immunity in a social organism. Here we use mass spectrometry-based quantitative proteomics to quantify nearly 800 proteins during the 5- to 6-day larval developmental stage, tracking their expression profiles.

Results
We report that honey bee larval growth is marked by an age-correlated increase of protein transporters and receptors, as well as protein nutrient stores, while opposite trends in protein translation activity and turnover were observed. Levels of the immunity factors prophenoloxidase and apismin are positively correlated with development, while others surprisingly were not significantly age-regulated, suggesting a molecular explanation for why bees are susceptible to major age-associated bee bacterial infections such as American Foulbrood or fungal diseases such as chalkbrood. Previously unreported findings include the reduction of antioxidant and G proteins in aging larvae.

Conclusion
These data have allowed us to integrate disparate findings in previous studies to build a model of metabolism and maturity of the immune system during larval development. This publicly accessible resource for protein expression trends will help generate new hypotheses in the increasingly important field of honey bee research.
Treatment of Pituitary-Dependent Cushing’s Disease with the Multireceptor Ligand Somatostatin Analog Pasireotide (SOM230): A Multicenter, Phase II Trial
Authors: Boscaro M. , Ludlam W. H. , Atkinson B. , Glusman J. E. , Petersenn S. , Reincke M. , Snyder P. , Tabarin A. , Biller B. M. K. , Findling J. , Melmed S. , Darby C. H. , Hu K. , Wang Y. , Freda P. U. , Grossman A. B. , Frohman L. A. , Bertherat J. 
Published: October 2008

Abstract
Context: There is currently no medical therapy for Cushing’s disease that targets the pituitary adenoma. Availability of such a medical therapy would be a valuable therapeutic option for the management of this disorder.
Objective: Our objective was to evaluate the short-term efficacy of the novel multireceptor ligand somatostatin analog pasireotide in patients with de novo, persistent, or recurrent Cushing’s disease.
Design: We conducted a phase II, proof-of-concept, open-label, single-arm, 15-d multicenter study.
Patients: Thirty-nine patients with either de novo Cushing’s disease who were candidates for pituitary surgery or with persistent or recurrent Cushing’s disease after surgery without having received prior pituitary irradiation.
Intervention: Patients self-administered sc pasireotide 600 μg twice daily for 15 d.
Main Outcome Measure: Normalization of urinary free cortisol (UFC) levels after 15 d treatment was the main outcome measure.
Results: Of the 29 patients in the primary efficacy analysis, 22 (76%) showed a reduction in UFC levels, of whom five (17%) had normal UFC levels (responders), after 15 d of treatment with pasireotide. Serum cortisol levels and plasma ACTH levels were also reduced. Steady-state plasma concentrations of pasireotide were achieved within 5 d of treatment. Responders appeared to have higher pasireotide exposure than nonresponders.
Conclusions: Pasireotide produced a decrease in UFC levels in 76% of patients with Cushing’s disease during the treatment period of 15 d, with direct effects on ACTH release. These results suggest that pasireotide holds promise as an effective medical treatment for this disorder.
Treatment with the Dipeptidyl Peptidase-4 Inhibitor Vildagliptin Improves Fasting Islet-Cell Function in Subjects with Type 2 Diabetes
Authors: D'Alessio David A. , Denney Amanda M. , Hermiller Linda M. , Prigeon Ronald L. , Martin Julie M. , Tharp William G. , Saylan Monica Liqueros , He YanLing , Dunning Beth E. , Foley James E. , Pratley Richard E. 
Published: October 2008

Abstract
Context: Dipeptidyl peptidase 4 (DPP-4) inhibitors are proposed to lower blood glucose in type 2 diabetes mellitus (T2DM) by prolonging the activity of the circulating incretins, glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1). Consistent with this mechanism of action, DPP-4 inhibitors improve glucose tolerance after meals by increasing insulin and reducing glucagon levels in the plasma. However, DPP-4 inhibitors also reduce fasting blood glucose, an unexpected effect because circulating levels of active GIP and GLP-1 are low in the postabsorptive state.
Objective: The objective of the study was to examine the effects of DPP-4 inhibition on fasting islet function.
Design: We conducted a randomized, double-blind, placebo-controlled trial.
Setting: The study was performed in General Clinical Research Centers at two University Hospitals.
Subjects: Forty-one subjects with T2DM were treated with metformin or diet, having good glycemic control with glycosylated hemoglobin values of 6.2–7.5%.
Intervention: Subjects were treated with vildagliptin (50 mg twice daily) or placebo for 3 months, followed by a 2-wk washout.
Major Outcome Measure: We measured insulin secretion in response to iv glucose and arginine before and after treatment and after drug washout.
Results: There were small and comparable reductions in glycosylated hemoglobin in both groups over 3 months. Vildagliptin increased fasting GLP-1 levels in subjects taking metformin, but not those managed with diet, and raised active GIP levels slightly. DPP-4 inhibitor treatment improved the acute insulin and C-peptide responses to glucose (50 and 100% respectively; P &lt; 0.05) and increased the slope of the C-peptide response to glucose (33%; P = 0.023).
Conclusion: Vildagliptin improves islet function in T2DM under fasting conditions. This suggests that DPP-4 inhibition has metabolic benefits in addition to enhancing meal-induced GLP-1 and GIP activity.
Lethal Respiratory Failure and Mild Primary Hypothyroidism in a Term Girl with a de Novo Heterozygous Mutation in the TITF1/NKX2.1 Gene
Authors: Maquet Emilie , Costagliola Sabine , Parma Jasmine , Christophe-Hobertus Christiane , Oligny Luc L. , Fournet Jean-Christophe , Robitaille Yves , Vuissoz Jean-Marc , Payot Antoine , Laberge Sophie , Vassart Gilbert , Van Vliet Guy , Deladoëy Johnny 
Published: October 2008

Abstract
Context: Thyroid transcription factor 1 (TITF1/NKX2.1) is expressed in the thyroid, lung, ventral forebrain, and pituitary. In the lung, TITF1/NKX2.1 activates the expression of genes critical for lung development and function. Titf/Nkx2.1−/− mice have pituitary and thyroid aplasia but also impairment of pulmonary branching. Humans with heterozygous TITF1/NKX2.1 mutations present with various combinations of primary hypothyroidism, respiratory distress, and neurological disorders.
Objective: The objective of the study was to report clinical and molecular studies of the first patient with lethal neonatal respiratory distress from a novel heterozygous TITF1/NKX2.1 mutation.
Participant: This girl, the first child of healthy nonconsanguineous French-Canadian parents, was born at 41 wk. Birth weight was 3460 g and Apgar scores were normal. Soon after birth, she developed acute respiratory failure with pulmonary hypertension. At neonatal screening on the second day of life, TSH was 31 mU/liter (N &lt;15) and total T4 245 nmol/liter (N = 120–350). Despite mechanical ventilation, thyroxine, surfactant, and pulmonary vasodilators, the patient died on the 40th day.
Results: Histopathology revealed pulmonary tissue with low alveolar counts. The thyroid was normal. Sequencing of the patient’s lymphocyte DNA revealed a novel heterozygous TITF1/NKX2.1 mutation (I207F). This mutation was not found in either parent. In vitro, the mutant TITF-1 had reduced DNA binding and transactivation capacity.
Conclusion: This is the first reported case of a heterozygous TITF1/NKX2.1 mutation leading to neonatal death from respiratory failure. The association of severe unexplained respiratory distress in a term neonate with mild primary hypothyroidism is the clue that led to the diagnosis.
These Lives Will Not Be Lost in Vain: Organizational Learning from Disaster in U.S. Coal Mining
Authors: Madsen Peter M. 
Published: October 2008

The stated purpose of the investigations that invariably follow industrial, transportation, and mining disasters is to learn from those tragedies to prevent future tragedies. But does prior experience with disaster make organizations more capable of preventing future disasters? Do organizations learn from disasters experienced by other organizations? Do organizations learn differently from rare disasters than they do from common minor accidents? In its present state, the organizational safety literature is poorly equipped to answer these questions. The present work begins to address this gap by empirically examining how prior organizational experience with disaster affects the likelihood that organizations will experience future disasters. It approaches the issue in the context of fatal U.S. coal mining accidents from 1983 to 2006. The analysis demonstrates that organizations do learn to prevent future disasters through both direct and vicarious experience with disaster. It also indicates that the mechanisms through which organizations learn from disasters differ from those through which they learn from minor accidents.
Role of Ambrisentan in the Management of Pulmonary Hypertension
Authors: Hrometz Sandra L , Shields Kelly M 
Published: October 2008

Objective: To review the role of ambrisentan in the treatment of pulmonary arterial hypertension (PAH). Data Sources: Literature was accessed through MEDLINE (1950-June 2008), Iowa Drug Information Service (1966–March 2008), EMBASE (1966-June 2008), bibliographies of pertinent articles, and unpublished data provided by the manufacturer and the Food and Drug Administration (FDA). Search terms included ambrisentan, endothelin antagonist, pulmonary hypertension, and pulmonary arterial hypertension. Due to limited literature available, additional criteria to limit searches were not used. Study Selection and Data Extraction: Abstracts and original preclinical and clinical research reports available in the English language were Identified for review. All manufacturer-provided data were also evaluated. Literature related to ambrisentan, endothelin antagonists, pulmonary hypertension, and pulmonary arterial hypertension were included. Four clinical trials evaluated the efficacy of ambrisentan in adults with symptomatic PAH. Data Synthesis: Ambrisentan is the latest endothelin-receptor antagonist (ERA) to obtain FDA approval for the treatment of PAH. It joins the first FDA-approved ERA, bosentan. Like bosentan, ambrisentan is available orally (with once-daily dosing compared with bosentan's twice-daily dosing) and has been shown to improve exercise capacity and delay clinical worsening. As with bosentan, the most significant safety concerns with ambrisentan relate to potential liver injury and a contraindication in pregnancy. Although ambrisentan has higher affinity for the endothelin type A receptor than for the endothelin type B receptor, specific advantages of this selectivity, in terms of efficacy compared with bosentan, a nonselective agent, have not been demonstrated. Conclusions: Ambrisentan has been shown to be an effective ERA in patients with PAH. A significant advantage of ambrisentan is the lack of any clinically important drug interactions with warfarin and sildenafil, which are frequently used by patients being treated for PAH.
Adverse Effects of Tenofovir Use in HIV-infected Pregnant Women and their Infants
Authors: Nurutdinova Diana , Onen Nur F , Hayes Ericka , Mondy Kristin , Overton E Turner 
Published: October 2008

Background: Data regarding use of tenofovir disopraxil fumarate in HIV-infected pregnant women are limited. Objective: To identify adverse effects of tenofovir use during pregnancy in HIV-infected women and their infants. Methods: In a retrospective case series, the charts of 127 pregnant HIV-infected women who received highly active antiretroviral therapy (HAART) between 2001 and 2005 were reviewed. Those who received tenofovir during pregnancy were selected for this study. Each woman's chart was reviewed for clinical data and adverse events during the pregnancy; each infant's chart was reviewed for growth parameters from birth to 12 months. Results: Fifteen HIV-infected women with limited treatment options were prescribed HAART containing tenofovir during 16 pregnancies. In utero tenofovir exposure was a median of 127 days (range 6–259). Tenofovir was well tolerated by all women throughout pregnancy. There were 15 successful deliveries occurring at a median (range) of 36 weeks (30–40), with a median birth weight of 3255 g (1135–3610). Complications, including 1 spontaneous abortion, occurred in 9 pregnancies and were not attributed to tenofovir. Eleven (73%) women had abnormal laboratory results, including 6 who experienced grade 1 hemoglobin abnormalities; 4 of these women had preexisting anemia. Calculated glomerular filtration rate (calculated by Modification of Diet in Renal Disease equation) remained above 90 mL/min/1.73 m2 in all women, except one who had a transient decline. Fourteen infants demonstrated normal growth and development for weight and height at birth, as well as during the 12-month follow-up period; no congenital malformations were documented. Mother-to-child transmission of HIV was not observed in this cohort. Conclusions: Tenofovir was found to be a well-tote rated component of HAART in this small cohort. Longer-term assessment of tenofovir effects on childhood growth and larger prospective studies of tenofovir use in pregnant women are warranted.
Choice of Comparator in Active Control Trials of New Drugs
Authors: Luijn Johan CF van , Loenen Arie C van , Gribnau Frank WJ , Leufkens Hubert GM 
Published: October 2008

Background: When choosing the active control group in a randomized that, it is important to maintain standard treatment for the therapeutic indication for which a medicine is studied. This choice is relevant not only for demonstrating the efficacy and safety of a new drug, but also for assessing Its place in therapy in comparison with existing medicines. Comparative information is important for decisions on prescribing and reimbursement. However, choosing the most suitable comparator is difficult when recommendations on drugs of first choice vary depending on clinical settings and times. Objective: To evaluate the choice of comparator in premarketing randomized active control trials (RaCTs) in comparison with recommendations lor standard treatment. Methods: We evaluated drugs that were authorized for use in the European Union market between 1999 and 2005. Information on active comparators in RaCTs was extracted from the European Public Assessment Reports and information on recommendations regarding standard treatment was retrieved from the annual editions of the Dutch reference book on pharmacotherapy. Data on prescribing and indications at the time of authorization and 3 years before authorization were included. The comparator was considered to be in line with standard treatment if there was a similarity in both active substance or therapeutic class and the dosage. Results: For 58 new medications identified, treatment in the active control group was in line with the recommended standard treatment in 108 of 153 (71%) RaCTs at the time of the drug's authorization; 47 (81%) of the new drugs had been compared with the recommended standard treatment in at least one trial. When dissimilarities occurred, none of the comparators had been recommended as standard treatment 3 years earlier (the supposed time of defining the trials' protocol). Conclusions: Most comparators in the premarketing RaCTs of new medicines were in line with the recommended standard treatment at the moment of marketing authorization. In view of this similarity, most of these trials are also fit for postmarketing decision-making on prescribing and on inclusion in clinical guidelines and reimbursement systems.
Use of Leflunomide in the Treatment of Polyomavirus BK-Associated Nephropathy
Authors: Wu Judy K , Harris Matthew T 
Published: October 2008

Objective: To review the available literature describing the use of leflunomide for the treatment of Polyomavirus BK-associated nephropathy (BKVAN) in renal transplant recipients. Data Sources: Relevant literature was obtained through MEDLINE (1950–May 2008) and Science Citation Index Expanded (1900–May 2008) by using search terms leflunomide, Arava, Polyomavirus, polyoma, BK virus, and transplant. Additional articles were identified through a manual search of the reference lists of the articles obtained. Study Selection and Data Extraction: All articles that were written in English and discussed leflunomide use for BKVAN In renal transplant recipients were evaluated. Case reports and in vitro studies were included in this review. Data Synthesis: BKVAN has emerged as a problematic infectious complication with limited treatment options in renal transplant recipients. Leflunomide, used off-label for refractory BKVAN, is postulated to possess both antiviral and immunosuppressive properties. Two in vitro culture studies, 5 case reports/series, 2 retrospective cohort studies, and 3 prospective observational trials that described leflunomide use in BKVAN were identified. Available literature suggests that leflunomide at target blood concentrations of around 40 mg/L, in addition to immunosuppressive reduction, reduces BK viremia/viruria and graft failure, with few dose-limiting adverse events. It is highly recommended that routine complete blood cell counts, hepatic function panels, and drug concentrations be monitored to detect toxicity. Conclusions: Leflunomide appears to be promising as adjunctive treatment of BKVAN in renal transplant patients. Due to the tack of controlled randomized trials, however, use of leflunomide as first-line treatment cannot be routinely recommended.