bluuebunny/crossref_metadata_2025_split huggingface dataset:
α-2,3-Sialyltransferase Expression Level Impacts the Kinetics of Lipooligosaccharide Sialylation, Complement Resistance, and the Ability of Neisseria gonorrhoeae to Colonize the Murine Genital Tract
Authors: Lewis Lisa A. , Gulati Sunita , Burrowes Elizabeth , Zheng Bo , Ram Sanjay , Rice Peter A. 
Published: February 2015

ABSTRACT Neisseria meningitidisandNeisseria gonorrhoeaemodify the terminal lacto-N-neotetraose moiety of their lipooligosaccharide (LOS) with sialic acid. N. gonorrhoeae LOS sialylation blocks killing by complement, which is mediated at least in part by enhanced binding of the complement inhibitor factor H (FH). The role of LOS sialylation in resistance of N. meningitidis to serum killing is less well defined. Sialylation in each species is catalyzed by the enzyme LOS α-2,3-sialyltransferase (Lst). Previous studies have shown increased Lst activity in N. gonorrhoeae compared to N. meningitidis due to an ~5-fold increase inlsttranscription. Using isogenic N. gonorrhoeae strains engineered to express gonococcallstfrom either the N. gonorrhoeae or N. meningitidislstpromoter, we show that decreased expression oflst(driven by the N. meningitidis promoter) reduced LOS sialylation as determined by less incorporation of tritium-labeled cytidine monophospho-N-acetylneuraminic acid (CMP-NANA; the donor molecule for sialic acid). Diminished LOS sialylation resulted in reduced rates of FH binding and increased pathway activation compared to N. gonorrhoeae promoter-drivenlstexpression. The N. meningitidislstpromoter generated sufficient Lst to sialylate N. gonorrhoeae LOSin vivo, and the level of sialylation after 24 h in the mouse genital tract was sufficient to mediate resistance to human serumex vivo. Despite demonstrable LOS sialylationin vivo, gonococci harboring the N. meningitidislstpromoter were outcompeted by those with the N. gonorrhoeaelstpromoter during coinfection of the vaginal tract of estradiol-treated mice. These data highlight the importance of highlstexpression levels for gonococcal pathogenesis.IMPORTANCE Neisseria gonorrhoeaehas become resistant to nearly every therapeutic antibiotic used and is listed as an “urgent threat” by the Centers for Disease Control and Prevention. Novel therapies are needed to combat drug-resistant N. gonorrhoeae. Gonococci express an α-2,3-sialyltransferase (Lst) that can scavenge sialic acid from the host and use it to modify lipooligosaccharide (LOS). Sialylation of gonococcal LOS converts serum-sensitive strains to serum resistance, decreases antibody binding, and combats killing by neutrophils and antimicrobial peptides. Mutant N. gonorrhoeae that lack Lst (cannot sialylate LOS) are attenuated in a mouse model. Lst expression levels differ among N. gonorrhoeae strains, and N. gonorrhoeae typically expresses more Lst thanNeisseria meningitidis. Here we examined the significance of differentiallstexpression levels and determined that the level of LOS sialylation is critical to the ability of N. gonorrhoeae to combat the immune system and survive in an animal model. LOS sialylation may be an ideal target for novel therapies.
Effect of once-daily indacaterol maleate/mometasone furoate on exacerbation risk in adolescent and adult asthma: a double-blind randomised controlled trial
Authors: Beasley Richard W , Donohue James F , Mehta Rajendra , Nelson Harold S , Clay Michelle , Moton Allen , Kim Han-Joo , Hederer Bettina M 
Published: February 2015

ObjectiveTo investigate the safety and efficacy of QMF149, a once-daily, fixed-dose combination of the long-acting β2-agonist (LABA) indacaterol maleate and inhaled corticosteroid (ICS) mometasone furoate (MF) for the treatment of persistent asthma. The hypothesis was that QMF149 would not increase the risk of serious asthma exacerbations.Setting174 research centres in nine countries.Participants1519 adolescents and adults with persistent asthma who were treated or qualified for treatment with combination LABA/ICS were randomised, and 1508 were included in the intention-to-treat analysis.InterventionPatients were randomised to QMF149 (indacaterol maleate 500 µg/MF 400 µg) or MF (400 µg) once daily via Twisthaler inhalation device in a double-blind, parallel-group study for 6–21 months.Primary and secondary outcome measuresThe primary end point was time to first serious asthma exacerbation (resulting in hospitalisation, intubation or death). The key secondary end point was annual rate of exacerbations requiring systemic corticosteroids.ResultsTreatment with QMF149 resulted in no significant difference in time to first serious exacerbation compared to MF (2 (0.3%) vs 6 events (0.8%); difference −0.52 percentage point; 95% CI −1.25 to 0.21, p=0.160, HR=0.31; 95% CI 0.06 to 1.54, p=0.151). QMF149 significantly reduced the annual rate of exacerbations requiring systemic corticosteroids (rate ratio=0.71; 95% CI 0.55 to 0.90, p=0.005). Proportions of patients experiencing adverse events were similar across groups (74.0% in the QMF149 group and 73.4% in the MF group). Serious adverse events occurred in 4% and 5.8% of patients in the QMF149 and MF groups, respectively.ConclusionsNo significant difference was observed in the primary outcome of time to first serious asthma exacerbation in patients treated with QMF149 compared with patients treated with MF. Long-term treatment with QMF149 once daily had a favourable safety/efficacy profile in adolescent and adult patients with persistent asthma.Trial registration numberClinicalTrials.gov;NCT00941798.
HIV research productivity and structural factors associated with HIV research output in European Union countries: a bibliometric analysis
Authors: Uusküla A , Toompere K , Laisaar K T , Rosenthal M , Pürjer M L , Knellwolf A , Läärä E , Des Jarlais D C 
Published: February 2015

ObjectivesTo assess HIV/AIDS research productivity in the 27 countries of the European Union (EU), and the structural level factors associated with levels of HIV/AIDS research productivity.MethodsA bibliometric analysis was conducted with systematic search methods used to locate HIV/AIDS research publications (period of 1 January 2002 to 31 December 2011; search databases: MEDLINE (Ovid, PubMed), EMBASE, ISI-Thomson Web of Science; no language restrictions).The publication rate (number of HIV/AIDS research publications per million population in 10 years) and the rate of articles published in HIV/AIDS journals and selected journals with moderate to very high (IF ≥3) 5-year impact factors were used as markers for HIV research productivity. A negative binomial regression model was fitted to assess the impact of structural level factors (sociodemographic, health, HIV prevalence and research/development indicators) associated with the variation in HIV research productivity.ResultsThe total numbers of HIV/AIDS research publications in 2002–2011 by country ranged from 7 to 9128 (median 319). The median publication rate (per million population in 10 years) was 45 (range 5–150) for all publications. Across all countries, 16% of the HIV/AIDS research was published in HIV/AIDS journals and 7% in selected journals with IF ≥3. Indicators describing economic (gross domestic product), demographic (size of the population) and epidemiological (HIV prevalence) conditions as well as overall scientific activity (total research output) in a country were positively associated with HIV research productivity.ConclusionsHIV research productivity varies noticeably across EU countries, and this variation is associated with recognisable structural factors.
Ultrasound-guided retrieval of lost intrauterine devices using very fine grasping forceps: a case series
Authors: Moro Francesca , Knez Jure , Pateman Katie , Derdelis Grigorios , Foo Xulin , Jurkovic Davor 
Published: February 2015

AimTo assess the efficacy of a novel ultrasound-guided procedure for the retrieval of intrauterine contraceptive devices (IUDs) when the threads are not visible at the external cervical os (‘lost threads’).MethodsThis was a prospective cohort study of consecutive women referred for ultrasound examination because of lost IUD threads. The procedures were performed under local anaesthesia in the outpatient setting. After injection of local anaesthetic, the anterior cervical lip was grasped with a vulsellum forceps. A 5Fr hysteroscopy grasping forceps was introduced transcervically into the uterine cavity under continuous transabdominal ultrasound guidance. The IUD was then grasped and removed from the uterus. Patients’ demographic data, gynaecological history, ultrasound findings, duration of procedure, success rate and pain score were recorded.ResultsTwenty-three consecutive women were included in the study. Ultrasound examination showed an IUD correctly sited in the centre of the uterine cavity in 20/23 (87%), in 2/23 (9%) it was partially embedded in the myometrium and in 1/23 (4%) the IUD was partially sited in the cervical canal. In 8/23 (35%) women the IUD threads were not visible on ultrasound scan. Removal of the IUD was successful in 22/23 (96%) cases with a median operating time of 3 (interquartile range 1.25–4.75) minutes. 15/23 (65%) women experienced no or minimal pain (pain score ≤3), 4/23 (17%) reported moderate pain (pain score 4–6) and 4/23 (17%) described the pain as severe (pain score 7–10). No complications were recorded during or immediately after the procedure.ConclusionsUltrasound-guided retrieval of lost IUDs using fine hysteroscopy grasping forceps is a highly successful technique and is well tolerated by women.
The Standard Molar Enthalpies of Formation of Nano‐ZnO Particles with Different Morphologies
Authors: Li Ya , Wu Xinmin 
Published: February 2015

The thermodynamic properties of nano‐ZnO particles with different morphologies were studied. First, based on the measurements of XRD and SEM, the morphologies of the five nano‐ZnO products were determined as sheet, block, sieve, column, and rod, and their particle size was about 40 nm. Then, based on a designed thermodynamic cycle, the standard molar enthalpies of formation of the nano‐ZnO particles were determined by the RD496‐2000 microcalorimeter, and they are (sheet) = (−337.43 ± 0.47) kJ·mol−1, (block) = (−336.57 ± 0.43) kJ·mol−1, (sieve) = (−337.04 ± 0.57) kJ·mol−1, (column) = (−343.56 ± 0.39) kJ·mol−1, and (rod) = (−341.43 ± 0.41) kJ·mol−1. The results show that the bigger difference of the morphologies of nano‐ZnO, the bigger difference of the standard molar enthalpies of formation.
CYP3A5 Functions as a Tumor Suppressor in Hepatocellular Carcinoma by Regulating mTORC2/Akt Signaling
Authors: Jiang Feng , Chen Lei , Yang Ying-Cheng , Wang Xian-ming , Wang Ruo-Yu , Li Liang , Wen Wen , Chang Yan-Xin , Chen Cai-Yang , Tang Jing , Liu Gao-Mi-Yang , Huang Wen-Tao , Xu Lin , Wang Hong-Yang 
Published: February 2015

Abstract
CYP3A5 is a cytochrome P450 protein that functions in the liver metabolism of many carcinogens and cancer drugs. However, it has not been thought to directly affect cancer progression. In this study, we challenge this perspective by demonstrating that CYP3A5 is downregulated in many hepatocellular carcinomas (HCC), where it has an important role as a tumor suppressor that antagonizes the malignant phenotype. CYP3A5 was downregulated in multiple cohorts of human HCC examined. Lower CYP3A5 levels were associated with more aggressive vascular invasion, poor differentiation, shorter time to disease recurrence after treatment, and worse overall patient survival. Mechanistic investigations showed that CYP3A5 overexpression limited MMP2/9 function and suppressed HCC migration and invasion in vitro and in vivo by inhibiting AKT signaling. Notably, AKT phosphorylation at Ser473 was inhibited in CYP3A5-overexpressing HCC cells, an event requiring mTORC2 but not Rictor/mTOR complex formation. CYP3A5-induced ROS accumulation was found to be a critical upstream regulator of mTORC2 activity, consistent with evidence of reduced GSH redox activity in most clinical HCC specimens with reduced metastatic capacity. Taken together, our results defined CYP3A5 as a suppressor of HCC pathogenesis and metastasis with potential utility a prognostic biomarker. Cancer Res; 75(7); 1470–81. ©2015 AACR.
BH3 Inhibitor Sensitivity and Bcl-2 Dependence in Primary Acute Lymphoblastic Leukemia Cells
Authors: Alford Sarah E. , Kothari Anisha , Loeff Floris C. , Eichhorn Joshua M. , Sakurikar Nandini , Goselink Henriette M. , Saylors Robert L. , Jedema Inge , Falkenburg J.H. Frederik , Chambers Timothy C. 
Published: February 2015

Abstract
BH3 mimetic drugs may be useful to treat acute lymphoblastic leukemia (ALL) but the sensitivity of primary tumor cells has not been fully evaluated. Here, B-lineage ALL cell cultures derived from a set of primary tumors were studied with respect to sensitivity to the BH3 mimetics ABT-263 and ABT-199 and to Bcl-2 dependence and function. These ALL cells each expressed high levels of Bcl-2 and exhibited great sensitivity to ABT-263 and ABT-199, which induced rapid apoptotic cell death. BH3 profiling indicated that the ALL cultures were Bcl-2 dependent. Coimmunoprecipitation studies revealed a multifaceted role for Bcl-2 in binding proapoptotic partners including Bax, Bak, Bik, and Bim. ABT-263 disrupted Bcl-2:Bim interaction in cells. Mcl-1 overexpression rendered ALL cells resistant to ABT-263 and ABT-199, with Mcl-1 assuming the role of Bcl-2 in binding Bim. Freshly isolated pediatric ALL blasts also expressed high levels of Bcl-2 and exhibited high sensitivity to Bcl-2 inhibition by the BH3 mimetic compounds. Overall, our results showed that primary ALL cultures were both more sensitive to BH3 mimetics and more uniform in their response than established ALL cell lines that have been evaluated previously. Furthermore, the primary cell model characterized here offers a powerful system for preclinical testing of novel drugs and drug combinations to treat ALL. Cancer Res; 75(7); 1366–75. ©2015 AACR.
Interaction between p53 Mutation and a Somatic HDMX Biomarker Better Defines Metastatic Potential in Breast Cancer
Authors: Grawenda Anna M. , Møller Elen K. , Lam Suzanne , Repapi Emmanouela , Teunisse Amina F.A.S. , Alnæs Grethe I.G. , Børresen-Dale Anne-Lise , Kristensen Vessela N. , Goding Colin R. , Jochemsen Aart G. , Edvardsen Hege , Bond Gareth L. 
Published: February 2015

Abstract
TP53 gene mutation is associated with poor prognosis in breast cancer, but additional biomarkers that can further refine the impact of the p53 pathway are needed to achieve clinical utility. In this study, we evaluated a role for the HDMX-S/FL ratio as one such biomarker, based on its association with other suppressor mutations that confer worse prognosis in sarcomas, another type of cancer that is surveilled by p53. We found that HDMX-S/FL ratio interacted with p53 mutational status to significantly improve prognostic capability in patients with breast cancer. This biomarker pair offered prognostic utility that was comparable with a microarray-based prognostic assay. Unexpectedly, the utility tracked independently of DNA-damaging treatments and instead with different tumor metastasis potential. Finally, we obtained evidence that this biomarker pair might identify patients who could benefit from anti-HDM2 strategies to impede metastatic progression. Taken together, our work offers a p53 pathway marker, which both refines our understanding of the impact of p53 activity on prognosis and harbors potential utility as a clinical tool. Cancer Res; 75(4); 698–708. ©2015 AACR.
Survivorship in Immune Therapy: Assessing Chronic Immune Toxicities, Health Outcomes, and Functional Status among Long-term Ipilimumab Survivors at a Single Referral Center
Authors: Johnson Douglas B. , Friedman Debra L. , Berry Elizabeth , Decker Ilka , Ye Fei , Zhao Shilin , Morgans Alicia K. , Puzanov Igor , Sosman Jeffrey A. , Lovly Christine M. 
Published: February 2015

Abstract
Ipilimumab, a novel immune checkpoint inhibitor, is associated with long-term survival in approximately 20% of patients with advanced melanoma and is also being evaluated in the adjuvant setting. With this growing cohort of survivors, long-term health outcomes, chronic toxicities, and functional outcomes among survivors treated with ipilimumab need to be defined. Using retrospective medical record abstraction, we evaluated disease status, chronic immune- and non–immune-related health events, pharmacologic management of symptoms, and functional status in patients with melanoma, with overall survival ≥2 years following ipilimumab treatment at Vanderbilt University. Ninety patients received ipilimumab for metastatic disease or as adjuvant therapy between January 2006 and September 2012, and 33 patients survived ≥2 years, with a median overall survival of 60.1 months. Of these, 24 patients were alive at the last follow-up (73%), with 14 patients free of disease (42%). Gastrointestinal and dermatologic adverse events were frequent but largely transient. By contrast, patients with hypophysitis universally required ongoing corticosteroids, although largely remained asymptomatic with appropriate hormone replacement. Surviving patients generally had excellent performance status (ECOG 0–1 in 23 of 24). Chronic neurologic toxicities caused substantial morbidity and mortality in 2 patients who received whole-brain radiotherapy &gt;5 years before analysis, and in one patient with chronic, painful peripheral neuropathy. No previously undescribed cardiac, pulmonary, gastrointestinal, hematologic, or neoplastic safety signals were identified. In conclusion, ipilimumab was associated with largely excellent functional outcomes among long-term survivors. Chronic endocrine dysfunction and occasional neurologic toxicity (primarily associated with whole-brain radiation) were observed in a small number of patients. Cancer Immunol Res; 3(5); 464–9. ©2015 AACR.
Differential Effect of B-Vitamin Therapy by Antiplatelet Use on Risk of Recurrent Vascular Events After Stroke
Authors: Arshi Baback , Ovbiagele Bruce , Markovic Daniela , Saposnik Gustavo , Towfighi Amytis 
Published: February 2015

Background and Purpose—
Although several randomized controlled trials failed to show a benefit of B vitamin therapy on composite outcomes of cardiovascular death, myocardial infarction, and stroke among individuals with elevated homocysteine, recent post hoc analyses have suggested that several factors may interact with the effects of vitamin treatment. One post hoc analysis revealed an interaction between B vitamin therapy and antiplatelet use; however, those results have not been replicated in other studies or populations.

Methods—
We conducted a post hoc analysis of the Vitamin Intervention for Stroke Prevention (VISP) trial, a randomized controlled trial evaluating treatment with high- versus low-dose B vitamin therapy for secondary prevention of vascular events among stroke survivors with elevated homocysteine. Cox regression models were used to assess primary (recurrent stroke) and secondary (stroke, myocardial infarction, or vascular death) outcomes among individuals on high- versus low-dose vitamin therapy, categorized by antiplatelet use, after adjusting for covariates.

Results—
Among 3680 participants, 52% took antiplatelet medications. When compared with low-dose therapy, high-dose vitamin therapy was associated with higher stroke risk among individuals on antiplatelets (hazard ratio, 1.43; 95% confidence interval, 1.02–2.01), but trended toward lower risk among those not on antiplatelets (hazard ratio, 0.86; 95% confidence interval, 0.62–1.19).

Conclusions—
High-dose B vitamin therapy may be associated with a higher risk of recurrent stroke among stroke survivors taking antiplatelets, but does not have a significant effect on recurrent stroke risk in those who are not on antiplatelets. Future randomized controlled trials may consider evaluating the effect of homocysteine lowering among stroke survivors with elevated homocysteine who are not on antiplatelet therapy.
Biomarkers and Mortality After Transient Ischemic Attack and Minor Ischemic Stroke
Authors: Greisenegger Stefan , Segal Helen C. , Burgess Annette I. , Poole Debbie L. , Mehta Ziyah , Rothwell Peter M. 
Published: February 2015

Background and Purpose—
Premature death after transient ischemic attack or stroke is more often because of heart disease or cancer than stroke. Previous studies found blood biomarkers not usefully predictive of nonfatal stroke but possibly of all-cause death. This association might be explained by potentially treatable occult cardiac disease or cancer. We therefore aimed to validate the association of a panel of biomarkers with all-cause death, particularly cardiac death and cancer death, despite the absence of associations with risk of nonfatal vascular events.

Methods—

Fifteen biomarkers were measured in 929 consecutive patients in a population-based study (Oxford Vascular Study), recruited from 2002 and followed up to 2013. Associations were determined by Cox regression. Model discrimination was assessed by
c
-statistic and the integrated discrimination improvement.

Results—

During 5560 patient-years of follow-up, none of the biomarkers predicted risk of nonfatal vascular events. However, soluble tumor necrosis factor α receptor-1, von Willebrand factor, heart-type fatty-acid-binding protein, and N-terminal pro-B-type natriuretic peptide were independently predictive of all-cause death (n=361; adjusted hazard ratio per SD, 95% confidence interval: heart-type fatty-acid-binding protein: 1.31, 1.12–1.56,
P
=0.002; N-terminal pro-B-type natriuretic peptide: 1.34, 1.11–1.62,
P
=0.002; soluble tumor necrosis factor α receptor-1: 1.45, 1.26–1.66,
P
=0.02; von Willebrand factor: 1.19, 1.04–1.36,
P
=0.01). The independent contribution of the four biomarkers taken together added prognostic information and improved model discrimination (integrated discrimination improvement=0.028,
P
=0.0001). N-terminal pro-B-type natriuretic peptide was most predictive of vascular death (adjusted hazard ratio=1.80, 95% confidence interval, 1.34–2.41,
P
<0.0001), whereas heart-type fatty-acid-binding protein predicted cancer deaths (1.64, 1.26–2.12,
P
=0.0002). Associations were strongest in patients without known prior cardiac disease or cancer.

Conclusions—
Several biomarkers predicted death of any cause after transient ischemic attack and minor stroke. N-terminal pro-B-type natriuretic peptide and heart-type fatty-acid-binding protein might improve patient selection for additional screening for occult cardiac disease or cancer, respectively. However, our results require validation in future studies.