bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phase II assessment of talabostat and cisplatin in second-line stage IV melanoma
Authors: Eager Robert M , Cunningham C Casey , Senzer Neil N , Stephenson Joe , Anthony Stephen P , O'Day Steven J , Frenette Gary , Pavlick Anna C , Jones Barry , Uprichard Margaret , Nemunaitis John 
Published: July 2009

Abstract

Background
Metastatic melanoma is an incurable disease with an average survival of less than one year. Talabostat is a novel dipeptidyl peptidase inhibitor with immunostimulatory properties.

Methods
This phase II, open label, single arm study was conducted to evaluate the safety and efficacy of 75–100 mg/m2 cisplatin combined with 300–400 mcg talabostat bid for 6, 21-day cycles. The primary endpoint was overall response. The rate of complete responses, duration of overall objective response, progression-free survival (PFS), and overall survival were the secondary endpoints.

Results
Six objective partial responses were recorded in the 74 patients (8.1%) in the intention-to-treat population. Five of these responses involved the 40 evaluable patients (12.5%). Thirty-one percent of patients reported SAEs to the combination of talabostat and cisplatin.

Conclusion
Acceptable tolerability was observed in the intention-to-treat population and antitumor activity was observed in 12.5% of evaluable patients, which is not greater than historical expectation with cisplatin alone.
Hydrogen bonding and packing density are factors most strongly connected to limiting sites of high flexibility in the 16S rRNA in the 30S ribosome
Authors: Huggins Wayne , Ghosh Sujit K , Wollenzien Paul 
Published: July 2009

Abstract

Background
Conformational flexibility in structured RNA frequently is critical to function. The 30S ribosomal subunit exists in different conformations in different functional states due to changes in the central part of the 16S rRNA. We are interested in evaluating the factors that might be responsible for restricting flexibility to specific parts of the 16S rRNA using biochemical data obtained from the 30S subunit in solution. This problem was approached taking advantage of the observation that there must be a high degree of conformational flexibility at sites where UV photocrosslinking occurs and a lack of flexibility inhibits photoreactivity at many other sites that are otherwise suitable for reaction.

Results
We used 30S x-ray structures to quantify the properties of the nucleotide pairs at UV- and UVA-s4U-induced photocrosslinking sites in 16S rRNA and compared these to the properties of many hundreds of additional sites that have suitable geometry but do not undergo photocrosslinking. Five factors that might affect RNA flexibility were investigated – RNA interactions with ribosomal proteins, interactions with Mg2+ ions, the presence of long-range A minor motif interactions, hydrogen bonding and the count of neighboring heavy atoms around the center of each nucleobase to estimate the neighbor packing density. The two factors that are very different in the unreactive inflexible pairs compared to the reactive ones are the average number of hydrogen bonds and the average value for the number of neighboring atoms. In both cases, these factors are greater for the unreactive nucleotide pairs at a statistically very significant level.

Conclusion
The greater extent of hydrogen bonding and neighbor atom density in the unreactive nucleotide pairs is consistent with reduced flexibility at a majority of the unreactive sites. The reactive photocrosslinking sites are clustered in the 30S subunit and this indicates nonuniform patterns of hydrogen bonding and packing density in the 16S rRNA tertiary structure. Because this analysis addresses inter-nucleotide distances and geometry between nucleotides distant in the primary sequence, the results indicate regional and global flexibility of the rRNA.
Bioassay guided purification of the antimicrobial fraction of a Brazilian propolis from Bahia state
Authors: Castro Myrella Lessio , Vilela Walquíria Ribeiro , Zauli Rogéria Cristina , Ikegaki Masaharu , Rehder Vera Lúcia Garcia , Foglio Mary Ann , de Alencar Severino Matias , Rosalen Pedro Luiz 
Published: July 2009

Abstract

Background
Brazilian propolis type 6 (Atlantic forest, Bahia) is distinct from the other types of propolis especially due to absence of flavonoids and presence of other non-polar, long chain compounds, but presenting good in vitro and in vivo antimicrobial activity. Several authors have suggested that fatty acids found in this propolis might be responsible for its antimicrobial activity; however, so far no evidence concerning this finding has been reported in the literature. The goals of this study were to evaluate the antibacterial activity of the main pure fatty acids in the ethanolic extract and fractions and elucidate the chemical nature of the bioactive compounds isolated from Brazilian propolis type 6.

Methods
Brazilian propolis type 6 ethanolic extract (EEP), hexane fraction (H-Fr), major fatty acids, and isolated sub-fractions were analyzed using high performance liquid chromatography (HPLC), high resolution gas chromatography with flame ionization detection (HRGC-FID), and gas chromatography-mass spectrometry (GC-MS). Three sub-fractions of H-Fr were obtained through preparative HPLC. Antimicrobial activity of EEP, H-Fr, sub-fractions, and fatty acids were tested against Staphyloccus aureus ATCC 25923 and Streptococcus mutans Ingbritt 1600 using minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC).

Results
EEP and H-Fr inhibited the growth of the microorganisms tested; nevertheless, no antimicrobial activity was found for the major fatty acids. The three sub-fractions (1, 2, and 3) were isolated from H-Fr by preparative HPLC and only sub-fraction 1 showed antimicrobial activity.

Conclusion
a) The major fatty acids tested were not responsible for the antimicrobial activity of propolis type 6; b) Sub-fraction 1, belonging to the benzophenone class, was responsible for the antimicrobial activity observed in the present study. The identification of the bioactive compound will improve the development of more efficient uses of this natural product.
An informatics model for guiding assembly of telemicrobiology workstations for malaria collaborative diagnostics using commodity products and open-source software
Authors: Suhanic West , Crandall Ian , Pennefather Peter 
Published: July 2009

Abstract

Background
Deficits in clinical microbiology infrastructure exacerbate global infectious disease burdens. This paper examines how commodity computation, communication, and measurement products combined with open-source analysis and communication applications can be incorporated into laboratory medicine microbiology protocols. Those commodity components are all now sourceable globally. An informatics model is presented for guiding the use of low-cost commodity components and free software in the assembly of clinically useful and usable telemicrobiology workstations.

Methods
The model incorporates two general principles: 1) collaborative diagnostics, where free and open communication and networking applications are used to link distributed collaborators for reciprocal assistance in organizing and interpreting digital diagnostic data; and 2) commodity engineering, which leverages globally available consumer electronics and open-source informatics applications, to build generic open systems that measure needed information in ways substantially equivalent to more complex proprietary systems. Routine microscopic examination of Giemsa and fluorescently stained blood smears for diagnosing malaria is used as an example to validate the model.

Results
The model is used as a constraint-based guide for the design, assembly, and testing of a functioning, open, and commoditized telemicroscopy system that supports distributed acquisition, exploration, analysis, interpretation, and reporting of digital microscopy images of stained malarial blood smears while also supporting remote diagnostic tracking, quality assessment and diagnostic process development.

Conclusion
The open telemicroscopy workstation design and use-process described here can address clinical microbiology infrastructure deficits in an economically sound and sustainable manner. It can boost capacity to deal with comprehensive measurement of disease and care outcomes in individuals and groups in a distributed and collaborative fashion. The workstation enables local control over the creation and use of diagnostic data, while allowing for remote collaborative support of diagnostic data interpretation and tracking. It can enable global pooling of malaria disease information and the development of open, participatory, and adaptable laboratory medicine practices. The informatic model highlights how the larger issue of access to generic commoditized measurement, information processing, and communication technology in both high- and low-income countries can enable diagnostic services that are much less expensive, but substantially equivalent to those currently in use in high-income countries.
Plasmodium falciparum enolase: stage-specific expression and sub-cellular localization
Authors: Pal Bhowmick Ipsita , Kumar Nirbhay , Sharma Shobhona , Coppens Isabelle , Jarori Gotam K 
Published: July 2009

Abstract

Background
In an earlier study, it was observed that the vaccination with Plasmodium falciparum enolase can confer partial protection against malaria in mice. Evidence has also build up to indicate that enolases may perform several non-glycolytic functions in pathogens. Investigating the stage-specific expression and sub-cellular localization of a protein may provide insights into its moonlighting functions.

Methods
Sub-cellular localization of P. falciparum enolase was examined using immunofluorescence assay, immuno-gold electron microscopy and western blotting.

Results
Enolase protein was detected at every stage in parasite life cycle examined. In asexual stages, enolase was predominantly (≥85–90%) present in soluble fraction, while in sexual stages it was mostly associated with particulate fraction. Apart from cytosol, enolase was found to be associated with nucleus, food vacuole, cytoskeleton and plasma membrane.

Conclusion
Diverse localization of enolase suggests that apart from catalyzing the conversion of 2-phosphoglycericacid into phosphoenolpyruvate in glycolysis, enolase may be involved in a host of other biological functions. For instance, enolase localized on the merozoite surface may be involved in red blood cell invasion; vacuolar enolase may be involved in food vacuole formation and/or development; nuclear enolase may play a role in transcription.
CCR5 signalling, but not DARC or D6 regulatory, chemokine receptors are targeted by herpesvirus U83A chemokine which delays receptor internalisation via diversion to a caveolin-linked pathway
Authors: Catusse Julie , Clark David J , Gompels Ursula A 
Published: July 2009

AbstractBackgroundHerpesviruses have evolved chemokines and chemokine receptors, which modulate the recruitment of human leukocytes during the inflammatory response to infection. Early post-infection, human herpesvirus 6A (HHV-6A) infected cells express the chemokine receptor U51A and chemokine U83A which have complementary effects in subverting the CC-chemokine family thereby controlling anti-viral leukocyte recruitment. Here we show that, to potentiate this activity, the viral chemokine can also avoid clearance by scavenger chemokine receptors, DARC and D6, which normally regulate an inflammatory response. Conversely, U83A delays internalisation of its signalling target receptor CCR5 with diversion to caveolin rich membrane domains. This mechanism can redirect displaced human chemokines to DARC and D6 for clearance of the anti-viral inflammatory response, leaving the viral chemokine unchecked.MethodsCell models for competitive binding assays were established using radiolabeled human chemokines and cold U83A on CCR5, DARC or D6 expressing cells. Flow cytometry was used to assess specific chemotaxis of CCR5 bearing cells to U83A, and internalisation of CCR5 specific chemokine CCL4 after stimulation with U83A. Internalisation analyses were supported by confocal microscopy of internalisation and co-localisation of CCR5 with caveosome marker caveolin-1, after virus or human chemokine stimulation.ResultsU83A displaced efficiently human chemokines from CCR5, with a high affinity of 0.01nM, but not from DARC or D6. Signalling via CCR5 resulted in specific chemoattraction of primary human leukocytes bearing CCR5. However, U83A effective binding and signalling to CCR5 resulted in delayed internalisation and recycling up to 2 hours in the absence of continual re-stimulation. This resulted in diversion to a delayed caveolin-linked pathway rather than the rapid clathrin mediated endocytosis previously shown with human chemokines CCL3 or CCL4.ConclusionU83A diverts human chemokines from signalling, but not regulatory or scavenger, receptors facilitating their clearance, while occupying signalling receptors at the cell surface. This can enhance virus specific inflammation, facilitating dissemination to replication sensitive leukocytes while evading clearance; this has implications for linked neuro-inflammatory pathologies.
Proteomic profiling of glucocorticoid-exposed myogenic cells: Time series assessment of protein translocation and transcription of inactive mRNAs
Authors: Reeves Erica KM , Gordish-Dressman Heather , Hoffman Eric P , Hathout Yetrib 
Published: July 2009

Abstract

Background
Prednisone, one of the most highly prescribed drugs, has well characterized effects on gene transcription mediated by the glucocorticoid receptor. These effects are typically occurring on the scale of hours. Prednisone also has a number of non-transcriptional effects (occurring on minutes scale) on protein signaling, yet these are less well studied. We sought to expand the understanding of acute effects of prednisone action on cell signaling using a combination of SILAC strategy and subcellular fractionations from C2C12 myotubes.

Results

De novo translation of proteins was inhibited in both SILAC labeled and unlabeled C2C12 myotubes. Unlabeled cells were exposed to prednisone while SILAC labeled cells remained untreated. After 0, 5, 15, and 30 minutes of prednisone exposure, labeled and unlabeled cells were mixed at 1:1 ratios and fractionated into cytosolic and nuclear fractions. A total of 534 proteins in the cytosol and 626 proteins in the nucleus were identified and quantitated, using 3 or more peptides per protein with peptide based probability ≤ 0.001. We identified significant increases (1.7- to 3.1- fold) in cytoplasmic abundance of 11 ribosomal proteins within 5 minutes of exposure, all of which returned to baseline by 30 min. We hypothesized that these drug-induced acute changes in the subcellular localization of the cell's protein translational machinery could lead to altered translation of quiescent RNAs. To test this, de novo protein synthesis was assayed after 15 minutes of drug exposure. Quantitative fluorography identified 16 2D gel spots showing rapid changes in translation; five of these were identified by MS/MS (pyruvate kinase, annexin A6 isoform A and isoform B, nasopharyngeal epithelium specific protein 1, and isoform 2 of Replication factor C subunit 1), and all showed the 5' terminal oligopyrimidine motifs associated with mRNA sequestration to and from inactive mRNA pools.

Conclusion
We describe novel approaches of subcellular proteomic profiling and assessment of acute changes on a minute-based time scale. These data expand the current knowledge of acute, non-transcriptional activities of glucocorticoids, including changes in protein subcellular localization, altered translation of quiescent RNA pools, and PKC-mediated cytoskeleton remodeling.
Age and gender differences in seven tests of functional mobility
Authors: Butler Annie A , Menant Jasmine C , Tiedemann Anne C , Lord Stephen R 
Published: July 2009

Abstract

Background
The objective of this study was to examine age and gender differences in seven tests of functional mobility.

Methods
The study included 50 young participants aged 20 to 39 years, and 684 older participants aged 75 to 98 years. Functional mobility measures included the coordinated stability test, the near tandem balance test, the six metre walk test, the sit to stand test with five repetitions, the alternate step test and the stair ascent and descent tests.

Results
Older participants performed significantly worse than the younger participants in all of the functional mobility tests (p < 0.001), with the older women performing worse than the older men in all of the tests (p < 0.05). Significant correlations were found within the older group among all the functional mobility tests scores (r = 0.24–0.87, p < 0.001), and between functional mobility performance and age (r = 0.14–0.35, p < 0.001). People with arthritis and stroke performed worse than people without these conditions in these tests.

Conclusion
This study provides a normative database for performance of young and older community-dwelling people in a battery of validated and reliable functional mobility tests. The results confirm age-related differences in functional mobility between young and older adults.
The prM-independent packaging of pseudotyped Japanese encephalitis virus
Authors: Lee Hee Jung , Min Kyung-Il , Lee Jungeun , Kang Sin-Hyung , Jeon Wonkyung , Nam Jae Hwan , Ju Young Ran , Kim Young Bong 
Published: July 2009

Abstract
As noted in other flaviviruses, the envelope (E) protein of Japanese encephalitis virus (JEV) interacts with a cellular receptor and mediates membrane fusion to allow viral entry into target cells, thus eliciting neutralizing antibody response. The formation of the flavivirus prM/E complex is followed by the cleavage of precursor membrane (prM) and membrane (M) protein by a cellular signalase. To test the effect of prM in JEV biology, we constucted JEV-MuLV pseudotyped viruses that express the prM/E protein or E only. The infectivity and titers of JEV pseudotyped viruses were examined in several cell lines. We also analyzed the neutralizing capacities with anti-JEV sera from JEV-immunized mice. Even though prM is crucial for multiple stages of JEV biology, the JEV-pseudotyped viruses produced with prM/E or with E only showed similar infectivity and titers in several cell lines and similar neutralizing sensitivity. These results showed that JEV-MuLV pseudotyped viruses did not require prM for production of infectious pseudotyped viruses.
Superior dislocation of the patella: a case report
Authors: Cusco Xavier , Seijas Roberto , Ares Oscar , Cugat Jose R , Garcia-Balletbo Montserrat , Cugat Ramon 
Published: July 2009

Abstract

Background
Superior dislocation of the patella is an uncommon condition that mainly occurs in knees with a high patella and medial femorotibial degenerative arthritis. There are no previous reports of this condition occurring in association with tibial valgus osteotomy. Case report: We report the case of a patient in whom vertical dislocation recurred twice at 4 months after tibial valgus osteotomy. To avert additional recurrence or new dislocations, the patient was treated surgically to remove the existing osteophytes. Conclusions: An arthroscopic approach was decided because of the lower associated morbidity and good results with this technique compared to open surgery.
ABT-869, a promising multi-targeted tyrosine kinase inhibitor: from bench to bedside
Authors: Zhou Jianbiao , Goh Boon-Cher , Albert Daniel H , Chen Chien-Shing 
Published: July 2009

Abstract
Tyrosine Kinase Inhibitors (TKI) have significantly changed the landscape of current cancer therapy. Understanding of mechanisms of aberrant TK signaling and strategies to inhibit TKs in cancer, further promote the development of novel agents.
ABT-869, a novel ATP-competitive receptor tyrosine kinase inhibitor is a potent inhibitor of members of the vascular endothelial growth factor (VEGF) and platelet derived growth factor (PDGF) receptor families. ABT-869 showed potent antiproliferative and apoptotic properties in vitro and in animal cancer xenograft models using tumor cell lines that were "addicted" to signaling of kinases targeted by ABT-869. When given together with chemotherapy or mTOR inhibitors, ABT-869 showed at least additive therapeutic effects. The phase I trial for ABT-869 was recently completed and it demonstrated respectable efficacy in solid tumors including lung and hepatocellular carcinoma with manageable side effects. Tumor cavitation and reduction of contrast enhancement after ABT-869 treatment supported the antiangiogenic activity. The correlative laboratory studies conducted with the trial also highlight potential biomarkers for future patient selection and treatment outcome.
Parallel to the clinical development, in vitro studies on ABT-869 resistance phenotype identified novel resistance mechanism that may be applicable to other TKIs. The future therapeutic roles of ABT-869 are currently been tested in phase II trials.
Medial patellofemoral ligament injury patterns and associated pathology in lateral patella dislocation: an MRI study
Authors: Guerrero Patrick , Li Xinning , Patel Ketan , Brown Michael , Busconi Brian 
Published: July 2009

AbstractBackgroundLateral Patella dislocations are common injuries seen in the active and young adult populations. Our study focus was to evaluate medial patellofemoral ligament (MPFL) injury patterns and associated knee pathology using Magnetic Resonance Imaging studies.MethodsMRI studies taken at one imaging site between January, 2007 to January, 2008 with the final diagnosis of patella dislocation were screened for this study. Of the 324 cases that were found, 195 patients with lateral patellar dislocation traumatic enough to cause bone bruises on the lateral femoral trochlea and the medial facet of the patella were selected for this study. The MRI images were reviewed by three independent observers for location and type of MPFL injury, osteochondral defects, loose bodies, MCL and meniscus tears. The data was analyzed as a single cohort and by gender.ResultsThis study consisted of 127 males and 68 females; mean age of 23 yrs. Tear of the MPFL at the patellar attachment occurred in 93/195 knees (47%), at the femoral attachment in 50/195 knees (26%), and at both the femoral and patella attachment sites in 26/195 knees (13%). Attenuation of the MPFL without rupture occurred in 26/195 knees (13%). Associated findings included loose bodies in 23/195 (13%), meniscus tears 41/195 (21%), patella avulsion/fracture in 14/195 (7%), medial collateral ligament sprains/tears in 37/195 (19%) and osteochondral lesions in 96/195 knees (49%). Statistical analysis showed females had significantly more associated meniscus tears than the males (27% vs. 17%, p = 0.04). Although not statistically significant, osteochondral lesions were seen more in male patients with acute patella dislocation (52% vs. 42%, p = 0.08).ConclusionPatients who present with lateral patella dislocation with the classic bone bruise pattern seen on MRI will likely rupture the MPFL at the patellar side. Females are more likely to have an associated meniscal tear than males; however, more males have underlying osteochondral lesions. Given the high percentage of associated pathology, we recommend a MRI of the knee in all patients who present with acute patella dislocation.