bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mass Spectrometric Analysis ofl-Cysteine Metabolism: Physiological Role and Fate ofl-Cysteine in the Enteric Protozoan Parasite Entamoeba histolytica
Authors: Jeelani Ghulam , Sato Dan , Soga Tomoyoshi , Watanabe Haruo , Nozaki Tomoyoshi 
Published: November 2014

ABSTRACTl-Cysteine is essential for virtually all living organisms, from bacteria to higher eukaryotes. Besides having a role in the synthesis of virtually all proteins and of taurine, cysteamine, glutathione, and other redox-regulating proteins,l-cysteine has important functions under anaerobic/microaerophilic conditions. In anaerobic or microaerophilic protozoan parasites, such asEntamoeba histolytica,l-cysteine has been implicated in growth, attachment, survival, and protection from oxidative stress. However, a specific role of this amino acid or related metabolic intermediates is not well understood. In this study, using stable-isotope-labeledl-cysteine and capillary electrophoresis-time of flight mass spectrometry, we investigated the metabolism ofl-cysteine inE. histolytica. [U-13C3,15N]l-cysteine was rapidly metabolized into three unknown metabolites, besidesl-cystine andl-alanine. These metabolites were identified as thiazolidine-4-carboxylic acid (T4C), 2-methyl thiazolidine-4-carboxylic acid (MT4C), and 2-ethyl-thiazolidine-4-carboxylic acid (ET4C), the condensation products ofl-cysteine with aldehydes. We demonstrated that these 2-(R)-thiazolidine-4-carboxylic acids serve for storage ofl-cysteine. Liberation ofl-cysteine occurred when T4C was incubated with amebic lysates, suggesting enzymatic degradation of thesel-cysteine derivatives. Furthermore, T4C and MT4C significantly enhanced trophozoite growth and reduced intracellular reactive oxygen species (ROS) levels when it was added to cultures, suggesting that 2-(R)-thiazolidine-4-carboxylic acids are involved in the defense against oxidative stress.IMPORTANCEAmebiasis is a human parasitic disease caused by the protozoan parasiteEntamoeba histolytica. In this parasite,l-cysteine is the principal low-molecular-weight thiol and is assumed to play a significant role in supplying the amino acid during trophozoite invasion, particularly when the parasites move from the anaerobic intestinal lumen to highly oxygenated tissues in the intestine and the liver. It is well known thatE. histolyticaneeds a comparatively high concentration ofl-cysteine for its axenic cultivation. However, the reason for and the metabolic fate ofl-cysteine in this parasite are not well understood. Here, using a metabolomic and stable-isotope-labeled approach, we investigated the metabolic fate of this amino acid in these parasites. We found thatl-cysteine inside the cell rapidly reacts with aldehydes to form 2-(R)-thiazolidine-4-carboxylic acid. We showed that these 2-(R)-thiazolidine-4-carboxylic derivatives serve as anl-cysteine source, promote growth, and protect cells against oxidative stress by scavenging aldehydes and reducing the ROS level. Our findings represent the first demonstration of 2-(R)-thiazolidine-4-carboxylic acids and their roles in protozoan parasites.
Deep Sequencing Identifies Noncanonical Editing of Ebola and Marburg Virus RNAs in Infected Cells
Authors: Shabman Reed S. , Jabado Omar J. , Mire Chad E. , Stockwell Timothy B. , Edwards Megan , Mahajan Milind , Geisbert Thomas W. , Basler Christopher F. 
Published: November 2014

ABSTRACT
Deep sequencing of RNAs produced by Zaire ebolavirus (EBOV) or the Angola strain of Marburgvirus (MARV-Ang) identified novel viral and cellular mechanisms that diversify the coding and noncoding sequences of viral mRNAs and genomic RNAs. We identified previously undescribed sites within the EBOV and MARV-Ang mRNAs where apparent cotranscriptional editing has resulted in the addition of non-template-encoded residues within the EBOV glycoprotein (GP) mRNA, the MARV-Ang nucleoprotein (NP) mRNA, and the MARV-Ang polymerase (L) mRNA, such that novel viral translation products could be produced. Further, we found that the well-characterized EBOV GP mRNA editing site is modified at a high frequency during viral genome RNA replication. Additionally, editing hot spots representing sites of apparent adenosine deaminase activity were found in the MARV-Ang NP 3′-untranslated region. These studies identify novel filovirus-host interactions and reveal production of a greater diversity of filoviral gene products than was previously appreciated.

IMPORTANCE
This study identifies novel mechanisms that alter the protein coding capacities of Ebola and Marburg virus mRNAs. Therefore, filovirus gene expression is more complex and diverse than previously recognized. These observations suggest new directions in understanding the regulation of filovirus gene expression.
Synthetic Biology for Engineering Acetyl Coenzyme A Metabolism in Yeast
Authors: Nielsen Jens 
Published: November 2014

ABSTRACT

The yeast
Saccharomyces cerevisiae
is a widely used cell factory for the production of fuels, chemicals, and pharmaceuticals. The use of this cell factory for cost-efficient production of novel fuels and chemicals requires high yields and low by-product production. Many industrially interesting chemicals are biosynthesized from acetyl coenzyme A (acetyl-CoA), which serves as a central precursor metabolite in yeast. To ensure high yields in production of these chemicals, it is necessary to engineer the central carbon metabolism so that ethanol production is minimized (or eliminated) and acetyl-CoA can be formed from glucose in high yield. Here the perspective of generating yeast platform strains that have such properties is discussed in the context of a major breakthrough with expression of a functional pyruvate dehydrogenase complex in the cytosol.
Improving incident reporting among junior doctors
Authors: Hotton Emily , Jordan Lesley , Peden Carol 
Published: November 2014

AbstractTo ensure systems in hospitals improve to make patient care safer, learning must occur when things go wrong. Incident reporting is one of the commonest mechanisms used to learn from harm events and near misses. Only a relatively small number of incidents that occur are actually reported and different groups of staff have different rates of reporting. Nationally, junior doctors are low reporters of incidents, a finding supported by our local data. We set out to explore the culture and awareness around incident reporting among our junior doctors, and to improve the incident reporting rate within this important staff group. In order to achieve this we undertook a number of work programmes focused on junior doctors, including: assessment of their knowledge, confidence and understanding of incident reporting, education on how and why to report incidents with a focus on reporting on clinical themes during a specific time period, and evaluation of the experience of those doctors who reported incidents.Junior doctors were asked to focus on incident reporting during a one week period. Before and after this focussed week, they were invited to complete a questionnaire exploring their confidence about what an incident was and how to report.Prior to "Incident Reporting Week", on average only two reports were submitted a month by junior doctors compared with an average of 15 per month following the education and awareness week. This project highlights the fact that using a focussed reporting period and/or specific clinical themes as an education tool can benefit a hospital by promoting awareness of incidents and by increasing incident reporting rates. This can only assist in improving hospital systems, and ultimately increase patient safety.
How clean is clean: a new approach to assess and enhance environmental cleaning and disinfection in an acute tertiary care facility
Authors: Ng Wai Khuan 
Published: November 2014

AbstractTraditional environmental cleaning monitoring through visual assessment can identify gross lapses in practice. However, in recent years the limitations underlying this need for ongoing compliance with cleaning and disinfection policies in the patient's immediate surroundings have become widely recognised.The value of objectively monitoring and improving environmental cleaning and disinfection in healthcare settings is becoming increasingly identified as a crucial element of strategies to mitigate the transmission of healthcare-associated infections. Mafraq Hospital has adopted a new method using an invisible fluorescent marker system to target on surfaces in patient’s immediate surroundings. Evaluation of at least 30 surfaces and objects in patient rooms revealed that only 11% of targets had been cleaned. Simulation training, educational interventions, empowerment, change involvement and acknowledgment were executed, leading to a sustained improvement of 77% in both quarter 2 and 3 of 2013 in cleaning and disinfecting of all surfaces and objects.
Cilostazol increases patency and reduces adverse outcomes in percutaneous femoropopliteal revascularisation: a meta-analysis of randomised controlled trials
Authors: Benjo Alexandre M , Garcia Daniel C , Jenkins J Stephen , Cardoso Rhanderson M N , Molina Taina P , El-Hayek Georges E , Nadkarni Girish N , Aziz Emad F , Dinicolantonio James J , Collins Tyrone 
Published: November 2014

BackgroundCilostazol is an oral antiplatelet agent currently indicated for treatment of intermittent claudication. There is evidence that cilostazol may reduce femoropopliteal restenosis after percutaneous endovascular intervention.MethodsWe searched PubMed, Scopus and Cochrane databases from 1966 through September 2013 for randomised controlled trials (RCTs) evaluating the addition of cilostazol to standard care in patients receiving femoropopliteal endovascular treatment. Restenosis, target lesion revascularisation and combined adverse outcomes (death, revascularisation and amputation) within 1–2 years postprocedure were evaluated.ResultsOf 205 articles, three RCTs were included in the analysis. The pooled data provided a total of 396 patients, 195 of whom received cilostazol. When compared to standard medical therapy alone, cilostazol significantly reduced the risk of restenosis (risk difference −0.20; 95% CI −0.29 to −0.11; p<0.0001; number needed to treat 5), target lesion revascularisation (risk difference −0.17; 95% CI −0.25 to −0.09; p<0.0001; number needed to treat 6). Death and amputation were not different in between groups.Conclusions and limitationCilostazol significantly increases femoropopliteal patency and decreases adverse outcomes in percutaneous endovascular intervention. However, further RCTs are needed because of limited sample size; this meta-analysis represents the best current evidence.
Bipartite portosystemic shunt with single insertion: a rare congenital vascular anomaly in a dog
Authors: Carlton Paul Francis , Hammond Gawain 
Published: November 2014

A case of a bipartite extra hepatic portosystemic shunt is described in a one‐year‐old, male entire Maltese Terrier breed dog. On CT angiography, one vessel was visibly a portocaval shunt with the other vessel arising from the splenic vein. Both vessels formed a single insertion to the caudal vena cava cranial to the right renal vein which was managed successfully surgically via placement of a 6 mm ameroid constrictor. Multiple portosystemic shunts in dogs have been reported but to the authors’ knowledge this is the first case of a bipartite origin, single insertion portosystemic shunt reported in a dog.
The Hallandia gneiss, a Swedish heritage stone resource
Authors: Schouenborg B. , Andersson J. , Göransson M. , Lundqvist Inger 
Published: November 2014

Abstract
Cited documents indicate that industrial production of building stones of the Hallandia gneiss from SW Sweden (Halland County) goes back to at least the 1850s when large quantities of paving stones were exported to Germany and Denmark. It is most likely that quarry operations have been going on for a much longer period, mostly for local needs.
The Hallandia gneiss is an aesthetically distinct gneiss unit characterized by multiple phases of deformation and veining at high-grade metamorphic conditions, unique with few, if any, equivalents in the world. Remnants of about 500 quarries (including small examples) have been documented in the area. The occurrence of Hallandia gneiss is limited to the coastal areas of SW Sweden where there are strong demands on the land for recreation and cultural heritage. The unique and restricted occurrence of the Hallandia gneiss to an area with strong competing interests of land use has resulted in severe concerns about the supply of this building stone material.
The need to safeguard a future supply of this rare stone type is urgent. This paper provides an outline of its unique geology, historic and present use, along with its technical and aesthetical properties.
A Noninvasive Procedure for Early-Stage Discrimination of Malignant and Precancerous Vocal Fold Lesions Based on Laryngeal Dynamics Analysis
Authors: Unger Jakob , Lohscheller Jörg , Reiter Maximilian , Eder Katharina , Betz Christian S. , Schuster Maria 
Published: November 2014

Abstract
About two thirds of laryngeal cancers originate at the vocal cords. Early-stage detection of malignant vocal fold alterations, including a discrimination of premalignant lesions, represents a major challenge in laryngology as precancerous vocal fold lesions and small carcinomas are difficult to distinguish by means of regular endoscopy only. We report a procedure to discriminate between malignant and precancerous lesions by measuring the characteristics of vocal fold dynamics by means of a computerized analysis of laryngeal high-speed videos. Ten patients with squamous cell T1a carcinoma, ten with precancerous lesions with hyperkeratosis, and ten subjects without laryngeal disease underwent high-speed laryngoscopy yielding 4,000 images per second. By means of wavelet-based phonovibrographic analysis, a set of three clinically meaningful vibratory measures was extracted from the videos comprising a total number of 15,000 video frames. Statistical analysis (ANOVA with post hoc two-sided t tests, P &lt; 0.05) revealed that vocal fold dynamics is significantly affected in the presence of precancerous lesions and T1a carcinoma. On the basis of the three measures, a discriminating pattern was extracted using a support vector machine-learning algorithm performing an individual classification in respect to the different clinical groups. By applying a leave-one-out cross-validation strategy, we could show that the proposed measures discriminate with a very high performance between precancerous lesions and T1a carcinoma (sensitivity, 100%; specificity, 100%). Although a large-scale study will be necessary to confirm clinical significance, the set of vibratory measures derived in this study may be applicable to improve the accuracy and reliability of noninvasive diagnostics of vocal fold lesions. Cancer Res; 75(1); 31–39. ©2014 AACR.
Cytotoxicity of Human Endogenous Retrovirus K–Specific T Cells toward Autologous Ovarian Cancer Cells
Authors: Rycaj Kiera , Plummer Joshua B. , Yin Bingnan , Li Ming , Garza Jeremy , Radvanyi Laszlo , Ramondetta Lois M. , Lin Kevin , Johanning Gary L. , Tang Dean G. , Wang-Johanning Feng 
Published: November 2014

Abstract
Purpose: To determine whether HERV-K envelope (ENV) protein could function as a tumor-associated antigen and elicit specific T-cell responses against autologous ovarian cancer cells.
Experimental Design: The expression of HERV-K transcripts and ENV protein, the presence of serum antibodies against HERV-K, reverse transcriptase (RT) activities, and cellular immune responses in primary ovarian cancer tissues and patient blood samples were analyzed and compared with samples from patients with benign ovarian diseases and normal female donors.
Results: Ovarian cancer cells in primary tumors and ascites expressed markers of cancer stem cells and markers of both mesenchymal and epithelial cells. Expression of HERV transcripts and HERV-K ENV protein and reverse transcriptase activities were higher in ovarian cancer compared with adjacent normal and benign tissues. The ovarian cancer patient plasma also had high reverse transcriptase activities and the ovarian cancer patient sera contained HERV-K immunoreactive antibodies. HERV-K–specific T cells generated from autologous dendritic cells pulsed with HERV-K ENV antigens exhibited phenotypes and functions consistent with a cellular immune response including T-cell proliferation, IFNγ production, and HERV-K–specific cytotoxic T lymphocyte (CTL) activity. Significantly higher CTL lysis of autologous tumor cells than of uninvolved normal cells was demonstrated in patients with ovarian cancer than patients with benign diseases and further enhanced lysis was observed if T regulatory cells were depleted.
Conclusion: Endogenous retroviral gene products in ovarian cancer may represent a potentially valuable new pool of tumor-associated antigens for targeting of therapeutic vaccines to ovarian cancer. Clin Cancer Res; 21(2); 471–83. ©2014 AACR.
Livin Contributes to Tumor Hypoxia–Induced Resistance to Cytotoxic Therapies in Glioblastoma Multiforme
Authors: Hsieh Chia-Hung , Lin Yu-Jung , Wu Chung-Pu , Lee Hsu-Tung , Shyu Woei-Cherng , Wang Chi-Chung 
Published: November 2014

Abstract
Purpose: Tumor hypoxia is one of the crucial microenvironments to promote therapy resistance (TR) in glioblastoma multiforme (GBM). Livin, a member of the family of inhibitor of apoptosis proteins, contributes antiapoptosis. However, the role of tumor hypoxia in Livin regulation and its impact on TR are unclear.
Experimental Design: Livin expression and apoptosis for tumor hypoxic cells derived from human glioblastoma xenografts or in vitro hypoxic stress-treated glioblastoma cells were determined by Western blotting, immunofluorescence imaging, and annexin V staining assay. The mechanism of hypoxia-induced Livin induction was investigated by chromatin immunoprecipitation assay and reporter assay. Genetic and pharmacologic manipulation of Livin was utilized to investigate the role of Livin on tumor hypoxia–induced TR in vitro or in vivo.
Results: The upregulation of Livin expression and downregulation of caspase activity were observed under cycling and chronic hypoxia in glioblastoma cells and xenografts, concomitant with increased TR to ionizing radiation and temozolomide. However, knockdown of Livin inhibited these effects. Moreover, hypoxia activated Livin transcription through the binding of hypoxia-inducible factor-1α to the Livin promoter. The targeted inhibition of Livin by the cell-permeable peptide (TAT-Lp15) in intracerebral glioblastoma-bearing mice demonstrated a synergistic suppression of tumor growth and increased the survival rate in standard-of-care treatment with radiation plus temozolomide.
Conclusions: These findings indicate a novel pathway that links upregulation of Livin to tumor hypoxia–induced TR in GBM and suggest that targeting Livin using cell-permeable peptide may be an effective therapeutic strategy for tumor microenvironment–induced TR. Clin Cancer Res; 21(2); 460–70. ©2014 AACR.
First-in-Human Phase I Study of Pictilisib (GDC-0941), a Potent Pan–Class I Phosphatidylinositol-3-Kinase (PI3K) Inhibitor, in Patients with Advanced Solid Tumors
Authors: Sarker Debashis , Ang Joo Ern , Baird Richard , Kristeleit Rebecca , Shah Krunal , Moreno Victor , Clarke Paul A. , Raynaud Florence I. , Levy Gallia , Ware Joseph A. , Mazina Kathryn , Lin Ray , Wu Jenny , Fredrickson Jill , Spoerke Jill M. , Lackner Mark R. , Yan Yibing , Friedman Lori S. , Kaye Stan B. , Derynck Mika K. , Workman Paul , de Bono Johann S. 
Published: November 2014

Abstract
Purpose: This first-in-human dose-escalation trial evaluated the safety, tolerability, maximal-tolerated dose (MTD), dose-limiting toxicities (DLT), pharmacokinetics, pharmacodynamics, and preliminary clinical activity of pictilisib (GDC-0941), an oral, potent, and selective inhibitor of the class I phosphatidylinositol-3-kinases (PI3K).
Patients and Methods: Sixty patients with solid tumors received pictilisib at 14 dose levels from 15 to 450 mg once-daily, initially on days 1 to 21 every 28 days and later, using continuous dosing for selected dose levels. Pharmacodynamic studies incorporated 18F-FDG-PET, and assessment of phosphorylated AKT and S6 ribosomal protein in platelet-rich plasma (PRP) and tumor tissue.
Results: Pictilisib was well tolerated. The most common toxicities were grade 1–2 nausea, rash, and fatigue, whereas the DLT was grade 3 maculopapular rash (450 mg, 2 of 3 patients; 330 mg, 1 of 7 patients). The pharmacokinetic profile was dose-proportional and supported once-daily dosing. Levels of phosphorylated serine-473 AKT were suppressed &gt;90% in PRP at 3 hours after dose at the MTD and in tumor at pictilisib doses associated with AUC &gt;20 h·μmol/L. Significant increase in plasma insulin and glucose levels, and &gt;25% decrease in 18F-FDG uptake by PET in 7 of 32 evaluable patients confirmed target modulation. A patient with V600E BRAF–mutant melanoma and another with platinum-refractory epithelial ovarian cancer exhibiting PTEN loss and PIK3CA amplification demonstrated partial response by RECIST and GCIG-CA125 criteria, respectively.
Conclusion: Pictilisib was safely administered with a dose-proportional pharmacokinetic profile, on-target pharmacodynamic activity at dose levels ≥100 mg and signs of antitumor activity. The recommended phase II dose was continuous dosing at 330 mg once-daily. Clin Cancer Res; 21(1); 77–86. ©2014 AACR.
Habitual Myofibrillar Protein Synthesis Is Normal in Patients with Upper GI Cancer Cachexia
Authors: MacDonald Alisdair J. , Johns Neil , Stephens Nathan , Greig Carolyn , Ross James A. , Small Alexandra C. , Husi Holger , Fearon Kenneth C. H. , Preston Tom 
Published: November 2014

Abstract
Purpose: Skeletal muscle wasting and weight loss are characteristic features of cancer cachexia and contribute to impaired function, increased morbidity, and poor tolerance of chemotherapy. This study used a novel technique to measure habitual myofibrillar protein synthesis in patients with cancer compared with healthy controls.
Experimental design: An oral heavy water (87.5 g deuterium oxide) tracer was administered as a single dose. Serum samples were taken over the subsequent week followed by a quadriceps muscle biopsy. Deuterium enrichment was measured in body water, serum alanine, and alanine in the myofibrillar component of muscle using gas chromatography–pyrolysis–isotope ratio mass spectrometry and the protein synthesis rate calculated from the rate of tracer incorporation. Net change in muscle mass over the preceding 3 months was calculated from serial CT scans and allowed estimation of protein breakdown.
Results: Seven healthy volunteers, 6 weight-stable, and 7 weight-losing (≥5% weight loss) patients undergoing surgery for upper gastrointestinal cancer were recruited. Serial CT scans were available in 10 patients, who lost skeletal muscle mass preoperatively at a rate of 5.6%/100 days. Myofibrillar protein fractional synthetic rate was 0.058%, 0.061%, and 0.073%/hour in controls, weight-stable, and weight-losing patients, respectively. Weight-losing patients had higher synthetic rates than controls (P = 0.03).
Conclusion: Contrary to previous studies, there was no evidence of suppression of myofibrillar protein synthesis in patients with cancer cachexia. Our finding implies a small increase in muscle breakdown may account for muscle wasting. Clin Cancer Res; 21(7); 1734–40. ©2014 AACR.