bluuebunny/crossref_metadata_2025 huggingface dataset:
Structural basis for catalytic activation of protein Z–dependent protease inhibitor (ZPI) by protein Z
Authors: Huang Xin , Yan Yahui , Tu Yizheng , Gatti Jeffrey , Broze George J. , Zhou Aiwu , Olson Steven T.
Published: July 2012

The anticoagulant serpin, protein Z-dependent protease inhibitor (ZPI), is catalytically activated by its cofactor, protein Z (PZ), to regulate the function of blood coagulation factor Xa on membrane surfaces. The X-ray structure of the ZPI-PZ complex has shown that PZ binds to a unique site on ZPI centered on helix G. In the present study, we show by Ala-scanning mutagenesis of the ZPI-binding interface, together with native PAGE and kinetic analyses of PZ binding to ZPI, that Tyr240 and Asp293 of ZPI are crucial hot spots for PZ binding. Complementary studies with protein Z–protein C chimeras show the importance of both pseudocatalytic and EGF2 domains of PZ for the critical ZPI interactions. To understand how PZ acts catalytically, we analyzed the interaction of reactive loop–cleaved ZPI (cZPI) with PZ and determined the cZPI X-ray structure. The cZPI structure revealed changes in helices A and G of the PZ-binding site relative to native ZPI that rationalized an observed 6-fold loss in PZ affinity and PZ catalytic action. These findings identify the key determinants of catalytic activation of ZPI by PZ and suggest novel strategies for ameliorating hemophilic states through drugs that disrupt the ZPI-PZ interaction.
The sixth sense: hematopoietic stem cells detect danger through purinergic signaling
Authors: Rossi Lara , Salvestrini Valentina , Ferrari Davide , Di Virgilio Francesco , Lemoli Roberto M.
Published: July 2012

Over the past decade, extracellular nucleotides (such as ATP and UTP) have emerged as key immunomodulators. This family of molecules, already known for its key metabolic functions, has been the focus of intense investigation that has unambiguously shown its crucial role as mediators of cell-to-cell communication. More recently, in addition to its involvement in inflammation and immunity, purinergic signaling has also been shown to modulate BM-derived stem cells. Extracellular nucleotides promote proliferation, CXCL12-driven migration, and BM engraftment of hematopoietic progenitor and stem cells. In addition, purinergic signaling acts indirectly on hematopoietic progenitor and stem cells by regulating differentiation and release of proinflammatory cytokines in BM-derived human mesenchymal stromal cells, which are part of the hematopoietic stem cell (HSC) niche. HSC research has recently blended into the field of immunology, as new findings highlighted the role played by immunologic signals (such as IFN-α, IFN-γ, or TNF-α) in the regulation of the HSC compartment. In this review, we summarize recent reports unveiling a previously unsuspected ability of HSCs to integrate inflammatory signals released by immune and stromal cells, with particular emphasis on the dual role of extracellular nucleotides as mediators of both immunologic responses and BM stem cell functions.
Genome-wide methylation profiling in decitabine-treated patients with acute myeloid leukemia
Authors: Yan Pearlly , Frankhouser David , Murphy Mark , Tam Hok-Hei , Rodriguez Benjamin , Curfman John , Trimarchi Michael , Geyer Susan , Wu Yue-Zhong , Whitman Susan P. , Metzeler Klaus , Walker Alison , Klisovic Rebecca , Jacob Samson , Grever Michael R. , Byrd John C. , Bloomfield Clara D. , Garzon Ramiro , Blum William , Caligiuri Michael A. , Bundschuh Ralf , Marcucci Guido
Published: July 2012

The outcome of older (≥ 60 years) acute myeloid leukemia (AML) patients is poor, and novel treatments are needed. In a phase 2 trial for older AML patients, low-dose (20 mg/m2 per day for 10 days) decitabine, a DNA hypomethylating azanucleoside, produced 47% complete response rate with an excellent toxicity profile. To assess the genome-wide activity of decitabine, we profiled pretreatment and post treatment (day 25/course 1) methylomes of marrow samples from patients (n = 16) participating in the trial using deep-sequencing analysis of methylated DNA captured by methyl-binding protein (MBD2). Decitabine significantly reduced global methylation compared with pretreatment baseline (P = .001). Percent marrow blasts did not correlate with global methylation levels, suggesting that hypomethylation was related to the activity of decitabine rather than to a mere decrease in leukemia burden. Hypomethylation occurred predominantly in CpG islands and CpG island-associated regions (P ranged from .03 to .04) A significant concentration (P < .001) of the hypomehtylated CpG islands was found in chromosome subtelomeric regions, suggesting a differential activity of decitabine in distinct chromosome regions. Hypermethylation occurred much less frequently than hypomethylation and was associated with low CpG content regions. Decitabine-related methylation changes were concordant with those previously reported in distinct genes. In summary, our study supports the feasibility of methylome analyses as a pharmacodynamic endpoint for hypomethylating therapies.
Brentuximab vedotin for relapsed or refractory CD30+ hematologic malignancies: the German Hodgkin Study Group experience
Authors: Rothe Achim , Sasse Stephanie , Goergen Helen , Eichenauer Dennis A. , Lohri Andreas , Jäger Ulrich , Bangard Christopher , Böll Boris , von Bergwelt Baildon Michael , Theurich Sebastian , Borchmann Peter , Engert Andreas
Published: July 2012

The CD30-targeting Ab-drug conjugate brentuximab vedotin (SGN-35) was recently approved for the treatment of relapsed Hodgkin lymphoma and anaplastic large-cell lymphoma by the Food and Drug Administration. In the present study, we report the experience of the German Hodgkin Study Group with brentuximab vedotin as single agent in 45 patients with refractory or relapsed CD30+ Hodgkin lymphoma who were treated either in a named patient program (n = 34) or in the context of a safety study associated with the registration program of this drug. In these very heavily pretreated patients, an objective response rate of 60%, including 22% complete remissions, could be documented. The median duration of response was 8 months. This retrospective analysis supports the previously reported excellent therapeutic efficacy of brentuximab vedotin in heavily pretreated CD30+ malignancies. This trial was registered at www.clinicaltrials.gov with identifier NCT01026233.
The sums of the reciprocals of Fibonacci polynomials and Lucas polynomials
Authors: Wu Zhengang , Zhang Wenpeng
Published: July 2012

In this article, we consider infinite sums derived from the reciprocals of the Fibonacci polynomials and Lucas polynomials, and infinite sums derived from the reciprocals of the square of the Fibonacci polynomials and Lucas polynomials. Then applying the floor function to these sums, we obtain several new equalities involving the Fibonacci polynomials and Lucas polynomials.

Mathematics Subject Classification (2010): Primary, 11B39.
Colon cancer associated genes exhibit signatures of positive selection at functionally significant positions
Authors: Morgan Claire C , Shakya Kabita , Webb Andrew , Walsh Thomas A , Lynch Mark , Loscher Christine E , Ruskin Heather J , O’Connell Mary J
Published: July 2012

Background

Cancer, much like most human disease, is routinely studied by utilizing model organisms. Of these model organisms, mice are often dominant. However, our assumptions of functional equivalence fail to consider the opportunity for divergence conferred by ~180 Million Years (MY) of independent evolution between these species. For a given set of human disease related genes, it is therefore important to determine if functional equivalency has been retained between species. In this study we test the hypothesis that cancer associated genes have different patterns of substitution akin to adaptive evolution in different mammal lineages.

Results

Our analysis of the current literature and colon cancer databases identified 22 genes exhibiting colon cancer associated germline mutations. We identified orthologs for these 22 genes across a set of high coverage (>6X) vertebrate genomes. Analysis of these orthologous datasets revealed significant levels of positive selection. Evidence of lineage-specific positive selection was identified in 14 genes in both ancestral and extant lineages. Lineage-specific positive selection was detected in the ancestral Euarchontoglires and Hominidae lineages for STK11, in the ancestral primate lineage for CDH1, in the ancestral Murinae lineage for both SDHC and MSH6 genes and the ancestral Muridae lineage for TSC1.

Conclusion

Identifying positive selection in the Primate, Hominidae, Muridae and Murinae lineages suggests an ancestral functional shift in these genes between the rodent and primate lineages. Analyses such as this, combining evolutionary theory and predictions - along with medically relevant data, can thus provide us with important clues for modeling human diseases.
Antibiotic prescribing in two private sector hospitals; one teaching and one non-teaching: A cross-sectional study in Ujjain, India
Authors: Sharma Megha , Eriksson Bo , Marrone Gaetano , Dhaneria Suryaprakash , Lundborg Cecilia Stålsby
Published: July 2012

Background

The worldwide increase in antibiotic resistant bacteria is of great concern. One of the main causes is antibiotic use which is likely to be high but is poorly described in India. The aim was to analyze and compare antibiotic prescribing for inpatients, in two private sector tertiary care hospitals; one Teaching and one Non-teaching, in Ujjain, India.

Methods

A cross-sectional study with manual data collection was carried out in 2008. Antibiotic prescribing was recorded for all inpatients throughout their hospital stay. Demographic profile of inpatients and prescribed antibiotics were compared. WHO Anatomical Therapeutic Chemical (ATC) classifications for antibiotics was used and Defined Daily Doses (DDD) were calculated per patient day.

Results

A total of 8385 inpatients were admitted during the study period. In the Teaching hospital (TH) 82% of 3004 and in the Non-teaching hospital (NTH) 79% of 5381 patients were prescribed antibiotics. The most commonly prescribed antibiotic groups were; fluoroquinolones and aminoglycosides in the TH and, 3rd generation cephalosporins and combination of antibiotics in the NTH. Of the prescriptions, 51% in the TH and 87% in the NTH (p<0.001) were for parenteral route administration. Prescribing by trade name was higher in the NTH (96%) compared with the TH (63%, p<0.001).

Conclusions

The results from both hospitals show extensive antibiotic prescribing. High use of combinations of antibiotics in the NTH might indicate pressure from pharmaceutical companies. There is a need to formulate and implement; based on local prescribing and resistance data; contextually appropriate antibiotic prescribing guidelines and a local antibiotic stewardship program.
Implementation of automated reporting of estimated glomerular filtration rate among Veterans Affairs laboratories: a retrospective study
Authors: Hall Rasheeda K , Wang Virginia , Jackson George L , Hammill Bradley G , Maciejewski Matthew L , Yano Elizabeth M , Svetkey Laura P , Patel Uptal D
Published: July 2012

Background

Automated reporting of estimated glomerular filtration rate (eGFR) is a recent advance in laboratory information technology (IT) that generates a measure of kidney function with chemistry laboratory results to aid early detection of chronic kidney disease (CKD). Because accurate diagnosis of CKD is critical to optimal medical decision-making, several clinical practice guidelines have recommended the use of automated eGFR reporting. Since its introduction, automated eGFR reporting has not been uniformly implemented by U. S. laboratories despite the growing prevalence of CKD. CKD is highly prevalent within the Veterans Health Administration (VHA), and implementation of automated eGFR reporting within this integrated healthcare system has the potential to improve care. In July 2004, the VHA adopted automated eGFR reporting through a system-wide mandate for software implementation by individual VHA laboratories. This study examines the timing of software implementation by individual VHA laboratories and factors associated with implementation.

Methods

We performed a retrospective observational study of laboratories in VHA facilities from July 2004 to September 2009. Using laboratory data, we identified the status of implementation of automated eGFR reporting for each facility and the time to actual implementation from the date the VHA adopted its policy for automated eGFR reporting. Using survey and administrative data, we assessed facility organizational characteristics associated with implementation of automated eGFR reporting via bivariate analyses.

Results

Of 104 VHA laboratories, 88% implemented automated eGFR reporting in existing laboratory IT systems by the end of the study period. Time to initial implementation ranged from 0.2 to 4.0 years with a median of 1.8 years. All VHA facilities with on-site dialysis units implemented the eGFR software (52%, p<0.001). Other organizational characteristics were not statistically significant.

Conclusions

The VHA did not have uniform implementation of automated eGFR reporting across its facilities. Facility-level organizational characteristics were not associated with implementation, and this suggests that decisions for implementation of this software are not related to facility-level quality improvement measures. Additional studies on implementation of laboratory IT, such as automated eGFR reporting, could identify factors that are related to more timely implementation and lead to better healthcare delivery.
Cisplatin and ultra-violet-C synergistically down-regulate receptor tyrosine kinases in human colorectal cancer cells
Authors: Kawaguchi Junji , Adachi Seiji , Yasuda Ichiro , Yamauchi Takahiro , Nakashima Masanori , Ohno Tomohiko , Shimizu Masahito , Yoshioka Takashi , Itani Masahiko , Kozawa Osamu , Moriwaki Hisataka
Published: July 2012

Background

Platinum-containing anti-cancer drugs such as cisplatin are widely used for patients with various types of cancers, however, resistance to cisplatin is observed in some cases. Whereas we have recently reported that high dose UV-C (200 J/m²) induces colorectal cancer cell proliferation by desensitization of EGFR, which leads oncogenic signaling in these cells, in this study we investigated the combination effect of low dose cisplatin (10 μM) and low dose UV-C (10 J/m²) on cell growth and apoptosis in several human colorectal cancer cells, SW480, DLD-1, HT29 and HCT116.

Results

The combination inhibited cell cycle and colony formation, while either cisplatin or UV-C alone had little effect. The combination also induced apoptosis in these cells. In addition, the combination caused the downregulation of EGFR and HER2. Moreover, UV-C alone caused the transient internalization of the EGFR, but with time EGFR recycled back to the cell surface, while cisplatin did not affect its localization. Surprisingly, the combination caused persistent internalization of the EGFR, which results in the lasting downregulation of the EGFR.

Conclusions

The combination of low dose cisplatin and low dose UV-C synergistically exerted anti-cancer effect by down-regulating RTK, such as EGFR and HER2. These findings may provide a novel strategy for the treatment of patients with colorectal cancer.
Proteomic analysis of the effects of exogenous calcium on hypoxic-responsive proteins in cucumber roots
Authors: He Lizhong , Lu Xiaomin , Tian Jing , Yang Yanjuan , Li Bin , Li Jing , Guo Shirong
Published: July 2012

Background

Hypoxia acts as a plant stress factor, particularly in cucumbers plants under hydroponic culture. Calcium is involved in stress signal transmission and in the growth of plants. To determine the effect of exogenous calcium on hypoxic-responsive proteins in cucumber (Cucumis sativus L. cv. Jinchun No.2) roots, proteomic analysis was performed using two-dimensional electrophoresis (2-DE) and mass spectrometry.

Results

Cucumber roots were used to analyze the influence of hypoxia on plants. The expressions of 38 protein spots corresponding to enzymes were shown to change in response to hypoxia. Of these, 30 spots were identified by matrix-assisted laser desorption/ionization-time of flight mass spectrometry (MALDI-TOF/TOF MS analysis). The proteins were categorized according to functional groups, including glycolysis, the tricarboxylic acid (TCA) cycle, fermentative metabolism, nitrogen metabolism, energy metabolism, protein synthesis and defense against stress. Exogenous calcium appeared to alleviate hypoxic stress via these metabolic and physiological systems. Western blotting was used to analyze the accumulation of alcohol dehydrogenase (ADH) and pyruvate decarboxylase (PDC); calcium further increased the expression of ADH and PDC under hypoxia. In addition, semi-quantitative reverse transcription-polymerase chain reaction (RT-PCR) was used to assess the transcript levels of differentially expressed proteins.

Conclusions

Exogenous calcium enhanced the expression of enzymes involved in glycolysis, the TCA cycle, fermentative metabolism, nitrogen metabolism, and reactive oxygen species (ROS) defense in plants under hypoxia. Calcium appears to induce hypoxic tolerance of cucumber seedlings. These phenomena have prompted us to further investigate the mechanisms by which cucumbers respond to exogenous calcium under hypoxia.
On the solutions of second order generalized difference equations
Authors: Manuel M MariaSusai , Kılıçman Adem , Xavier G BrittoAntony , Pugalarasu R , Dilip DS
Published: July 2012

In this article, the authors discuss

ℓ

2
(
ℓ
)

and

c

0
(
ℓ
)

solutions of the second order generalized difference equation

Δ
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2

u
(
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+
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(
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u
(
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)

=
0
,

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∈
[
a
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)
,
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0

and we prove the condition for non existence of non-trivial solution where

Δ
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u
(
k
)
=
u
(
k
+
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)
−
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(
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for

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. Further we present some formulae and examples to find the values of finite and infinite series in number theory as application of

Δ
ℓ

.

MSC:39A12, 39A70, 47B39, 39B60.
Antiviral activity of Bifidobacterium adolescentisSPM1005-A on human papillomavirus type 16
Authors: Cha Min-Kyeong , Lee Do-Kyung , An Hyang-Mi , Lee Si-Won , Shin Seon-Hee , Kwon Jeong-Hyun , Kim Kyung-Jae , Ha Nam-Joo
Published: July 2012

Background

Probiotic lactic acid bacteria (LAB) support a functional and balanced immune system, and contribute to immune modulatory effects in combatting microbial pathogens, including viruses. Most cervical cancers are associated with anogenital region infection with high-risk (HR) human papillomavirus (HPV). In this study, we analyzed the antiviral activity of Bifidobacterium adolescentis SPM1005-A in the SiHa cervical cancer cell line expressing HPV type 16.

Methods

We assessed the cellular toxicity of B. adolescentis SPM1005-A in SiHa cells by the Trypan blue dye exclusion assay. Cells (3.6 × 105) in culture plates with or without B. adolescentis SPM1005-A in the same type of medium, were incubated with HPV type 16 at a concentration of 5.1 × 107 cfu/ml. For antiviral analysis, we performed quantitative real-time PCR (qRT-PCR) for E6 and E7 oncogene expressions and observed protein levels by immunoblotting.

Results

The qRT-PCR results showed that E6 and E7 mRNA levels decreased simultaneously. Western blot analysis revealed that the E6 protein expression slightly decreased after 24 and 48 h, but the level of E7 protein expression appear unaffected compared with that in the control. Decreased HPV16 E6 and E7 mRNA transcript and protein levels were not associated with cell morphology or significant cytotoxic effects.

Conclusions

This study showed that B. adolescentis SPM1005-A had antiviral activity through suppression E6 and E7 oncogene expression. The results suggest that B. adolescentis SPM1005-A could be potential applications of HPV-associated cervical cancer prevention.
P2X7 signaling promotes microsphere embolism-triggered microglia activation by maintaining elevation of Fas ligand
Authors: Lu Ying-mei , Tao Rong-rong , Huang Ji-yun , Li Li-tao , Liao Mei-hua , Li Xiao-ming , Fukunaga Kohji , Hong Ze-Hui , Han Feng
Published: July 2012

Background

The cerebral microvascular occlusion elicits microvascular injury which mimics the different degrees of stroke severity observed in patients, but the mechanisms underlying these embolic injuries are far from understood. The Fas ligand (FasL)-Fas system has been implicated in a number of pathogenic states. Here, we examined the contribution of microglia-derived FasL to brain inflammatory injury, with a focus on the potential to suppress the FasL increase by inhibition of the P2X7-FasL signaling with pharmacological or genetic approaches during ischemia.

Methods

The cerebral microvascular occlusion was induced by microsphere injection in experimental animals. Morphological changes in microglial cells were studied immunohistochemically. The biochemical analyses were used to examine the intracellular changes of P2X7/FasL signaling. The BV-2 cells and primary microglia from mice genetically deficient in P2X7 were used to further establish a linkage between microglia activation and FasL overproduction.

Results

The FasL expression was continuously elevated and was spatiotemporally related to microglia activation following microsphere embolism. Notably, P2X7 expression concomitantly increased in microglia and presented a distribution pattern that was similar to that of FasL in ED1-positive cells at pathological process of microsphere embolism. Interestingly, FasL generation in cultured microglia cells subjected to oxygen-glucose deprivation-treated neuron-conditioned medium was prevented by the silencing of P2X7. Furthermore, FasL induced the migration of BV-2 microglia, whereas the neutralization of FasL with a blocking antibody was highly effective in inhibiting ischemia-induced microglial mobility. Similar results were observed in primary microglia from wild-type mice or mice genetically deficient in P2X7. Finally, the degrees of FasL overproduction and neuronal death were consistently reduced in P2X7
−/− mice compared with wild-type littermates following microsphere embolism insult.

Conclusion

FasL functions as a key component of an immunoreactive response loop by recruiting microglia to the lesion sites through a P2X7-dependent mechanism. The specific modulation of P2X7/FasL signaling and aberrant microglial activation could provide therapeutic benefits in acute and subacute phase of cerebral microembolic injury.
Peer relations scale for adolescents treated for substance use disorder: a factor analytic presentation
Authors: Yao Ping , Ciesla James R , Mazurek Kathryn D , Spear Sherilynn F
Published: July 2012

Background

The literature indicates that peer relations are an important aspect of the treatment and recovery of adolescents with substance use disorder (SUD). Unfortunately, no standard measure of peer relations exists. The objective of this research is to use exploratory factor analysis to examine the underlying factor structure of a 14-item peer relations scale for use in this treatment population.

Methods

Participants are 509 adolescents discharged from primary substance abuse treatment from 2003–2010. The data are from research conducted between six and twelve months post discharge via a 230-item questionnaire that included the 14-item peer relations scale. The scale has questions that assess the degree to which the adolescent's social contacts conform to norms of positive behavior and therefore foster non-use and recovery. The response rate was 62%.

Results

The scale was decomposed by principal component factor analysis. When the matrix was rotated by varimax a three factor solution explaining 99.99% of the common variance emerged. The first factor yielded ten items that measure association with peers who engage in positive versus delinquent social behavior (positive versus negative social behavior). The three items in the second factor specify association with peers who use versus those who don’t use drugs, and thereby encourage recovery and discourage drug use (drug use). The third and factor contained two items measuring the degree to which the recovering adolescent associates with new or previous friends (post treatment peer association).

Conclusions

This scale is useful as a standard measure in that it begins to identify the measurable dimensions of peer relations that influence sustaining post treatment recovery.
Sphingosine kinase/sphingosine 1-phosphate axis: a new player for insulin-like growth factor-1-induced myoblast differentiation
Authors: Bernacchioni Caterina , Cencetti Francesca , Blescia Sabrina , Donati Chiara , Bruni Paola
Published: July 2012

Background

Insulin-like growth factor-1 (IGF-1) is the most important physiological regulator of skeletal muscle progenitor cells, which are responsible for adult skeletal muscle regeneration. The ability of IGF-1 to affect multiple aspects of skeletal muscle cell biology such as proliferation, differentiation, survival and motility is well recognized, although the molecular mechanisms implicated in its complex biological action are not fully defined. Since sphingosine 1-phosphate (S1P) has recently emerged as a key player in skeletal muscle regeneration, we investigated the possible involvement of the sphingosine kinase (SK)/S1P receptor axis on the biological effects of IGF-1 in murine myoblasts.

Methods

RNA interference, chemical inhibition and immunofluorescence approaches were used to assess the role of the SK/S1P axis on the myogenic and mitogenic effects of IGF-1 in C2C12 myoblasts.

Results

We show that IGF-1 increases SK activity in mouse myoblasts. The effect of the growth factor does not involve transcriptional regulation of SK1 or SK2, since the protein content of both isoforms is not affected; rather, IGF-1 enhances the fraction of the active form of SK. Moreover, transactivation of the S1P2 receptor induced by IGF-1 via SK activation appears to be involved in the myogenic effect of the growth factor. Indeed, the pro-differentiating effect of IGF-1 in myoblasts is impaired when SK activity is pharmacologically inhibited, or SK1 or SK2 are specifically silenced, or the S1P2 receptor is downregulated. Furthermore, in this study we show that IGF-1 transactivates S1P1/S1P3 receptors via SK activation and that this molecular event negatively regulates the mitogenic effect elicited by the growth factor, since the specific silencing of S1P1 or S1P3 receptors increases cell proliferation induced by IGF-1.

Conclusions

We demonstrate a dual role of the SK/S1P axis in response to myoblast challenge with IGF-1, that likely is important to regulate the biological effect of this growth factor. These findings add new information to the understanding of the mechanism by which IGF-1 regulates skeletal muscle regeneration.
Polymorphisms in cytochrome P450 2C19 enzyme and cessation of leflunomide in patients with rheumatoid arthritis
Authors: Wiese Michael D , Schnabl Matthew , O'Doherty Catherine , Spargo Llewellyn D , Sorich Michael J , Cleland Leslie G , Proudman Susanna M
Published: July 2012

Introduction

Rational selection of disease modifying anti-rheumatic drugs in the treatment of rheumatoid arthritis (RA) has many potential advantages, including rapid disease control, reduced long-term disability and reduced overall cost to the healthcare system. Inter-individual genetic differences are particularly attractive as markers to predict efficacy and toxicity, as they can be determined rapidly prior to drug selection. The aims of this study, therefore, were to investigate the association between differences in genes associated with the metabolism, clearance and efficacy of leflunomide with its cessation in a group of rheumatoid arthritis patients who were treated with an intensive contemporary, treat-to-target approach.

Methods

This retrospective cohort study identified all individuals who received leflunomide and were enrolled in the Early Arthritis inception cohort at the Royal Adelaide Hospital between 2001 and July 2011. Inclusion criteria were age (>18) and a diagnosis of rheumatoid arthritis. Patients were excluded if a DNA sample was not available, if they withdrew from the cohort or if clinical data were insufficient. Subjects were followed for 12 months or until either another disease modifying antirheumatic drug was added or leflunomide was ceased. The following single nucleotide polymorphisms (SNPs) were determined: CYP2C19*2 (rs4244285), CYP2C19*17 (rs12248560), ABCG2 421C>A (rs2231142), CYP1A2*1F (rs762551) and DHODH 19C>A (rs3213422). The effects of variables on cessation were assessed with Cox Proportional Hazard models.

Results

Thirty-three of 78 (42.3%) patients ceased leflunomide due to side effects. A linear trend between cytochrome P450 2C19 (CYP2C19) phenotype and leflunomide cessation was observed, with poor and intermediate metabolizers ceasing more frequently (adjusted Hazard Ratio = 0.432 for each incremental change in phenotype, 95% CI 0.237 to 0.790, P = 0.006). Previously observed associations between cytochrome P450 1A2 (CYP1A2) and dihydro-orotate dehydrogenase (DHODH) genotype and toxicity were not apparent, but there was a trend for ATP-binding cassette sub-family G member 2 (ABCG2) genotype to be associated with cessation due to diarrhea.

Conclusions

CYP2C19 phenotype was associated with cessation due to toxicity, and since CYP2C19 intermediate and poor metabolizers have lower teriflunomide concentrations, it is likely that they have a particularly poor risk:benefit ratio when using this drug.
Fibroblast-secreted hepatocyte growth factor mediates epidermal growth factor receptor tyrosine kinase inhibitor resistance in triple-negative breast cancers through paracrine activation of Met
Authors: Mueller Kelly L , Madden Julie M , Zoratti Gina L , Kuperwasser Charlotte , List Karin , Boerner Julie L
Published: July 2012

Introduction

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have shown clinical efficacy in lung, colon, and pancreatic cancers. In lung cancer, resistance to EGFR TKIs correlates with amplification of the hepatocyte growth factor (HGF) receptor tyrosine kinase Met. Breast cancers do not respond to EGFR TKIs, even though EGFR is overexpressed. This intrinsic resistance to EGFR TKIs in breast cancer does not correlate with Met amplification. In several tissue monoculture models of human breast cancer, Met, although expressed, is not phosphorylated, suggesting a requirement for a paracrine-produced ligand. In fact, HGF, the ligand for Met, is not expressed in epithelial cells but is secreted by fibroblasts in the tumor stroma. We have identified a number of breast cancer cell lines that are sensitive to EGFR TKIs. This sensitivity is in conflict with the observed clinical resistance to EGFR TKIs in breast cancers. Here we demonstrate that fibroblast secretion of HGF activates Met and leads to EGFR/Met crosstalk and resistance to EGFR TKIs in triple-negative breast cancer (TNBC).

Methods

The SUM102 and SUM149 TNBC cell lines were used in this study. Recombinant HGF as well as conditioned media from fibroblasts expressing HGF were used as sources for Met activation. Furthermore, we co-cultured HGF-secreting fibroblasts with Met-expressing cancer cells to mimic the paracrine HGF/Met pathway, which is active in the tumor microenvironment. Cell growth, survival, and transformation were measured by cell counting, clonogenic and MTS assays, and soft agar colony formation, respectively. Student's t test was used for all statistical analysis.

Results

Here we demonstrate that treatment of breast cancer cells sensitive to EGFR TKIs with recombinant HGF confers a resistance to EGFR TKIs. Interestingly, knocking down EGFR abrogated HGF-mediated cell survival, suggesting a crosstalk between EGFR and Met. HGF is secreted as a single-chain pro-form, which has to be proteolytically cleaved in order to activate Met. To determine whether the proteases required to activate pro-HGF were present in the breast cancer cells, we utilized a fibroblast cell line expressing pro-HGF (RMF-HGF). Addition of pro-HGF-secreting conditioned fibroblast media to TNBC cells as well as co-culturing of TNBC cells with RMF-HGF fibroblasts resulted in robust phosphorylation of Met and stimulated proliferation in the presence of an EGFR TKI.

Conclusions

Taken together, these data suggest a role for Met in clinical resistance to EGFR TKIs in breast cancer through EGFR/Met crosstalk mediated by tumor-stromal interactions.
The impact of statin use on pneumonia risk and outcome: a combined population-based case-control and cohort study
Authors: Nielsen Anders Gunnar , Nielsen Rikke Beck , Riis Anders Hammerich , Johnsen Søren Paaske , Sørensen Henrik Toft , Thomsen Reimar Wernich
Published: July 2012

Introduction

The impact of statin use on pneumonia risk and outcome remains unclear. We therefore examined this risk in a population-based case-control study and did a 5-year update of our previous 30-day mortality analyses.

Methods

We identified 70,953 adults with a first-time hospitalization for pneumonia between 1997 and 2009 in Northern Denmark. Ten age- and sex-matched population controls were selected for each pneumonia patient. To control for potential confounders, we retrieved individual-level data on other medications, comorbidities, recent surgery, socioeconomic indicators, influenza vaccination, and other markers of frailty or health awareness from medical databases. We followed all pneumonia patients for 30 days after hospital admission.

Results

A total of 7,223 pneumonia cases (10.2%) and 64 523 controls (9.1%) were statin users before admission, corresponding to an age- and sex-matched odds ratio (OR) of 1.17 (95% confidence interval [CI]: 1.14-1.21). After controlling for higher comorbidity and a wide range of other potential confounders, the adjusted OR for pneumonia associated with current statin use dropped to 0.80 (95% CI: 0.77-0.83). Previous statin use was not associated with decreased pneumonia risk (adjusted OR = 0.97, 95% CI: 0.91-1.02). Decreased risk remained significant after further adjustment for frailty and health awareness markers.

The prevalence of statin use among Danish pneumonia patients increased from 1% in 1997 to 24% in 2009. Thirty-day mortality following pneumonia hospitalization was 11.3% among statin users versus 15.1% among nonusers. This corresponded to a 27% reduced mortality rate (adjusted hazard ratio = 0.73, 95% CI: 0.67-0.79), corroborating our earlier findings.

Conclusions

Current statin use was associated with both a decreased risk of hospitalization for pneumonia and lower 30-day mortality following pneumonia.
The HIV-1 protease inhibitor nelfinavir activates PP2 and inhibits MAPK signaling in macrophages: a pathway to reduce inflammation
Authors: Wallet Mark A , Reist Caroline M , Williams Julie C , Appelberg Sofia , Guiulfo Giorgio L , Gardner Brent , Sleasman John W , Goodenow Maureen M
Published: July 2012

Nelfinavir has anti-inflammatory effects directly upon human macrophages independent of antiviral activity.

The HIV-1 PI NFV has off-target effects upon host enzymes, including inhibition of the 20S proteasome, resulting in activation of PP1. HIV-1-associated monocyte/macrophage activation, in part a result of systemically elevated levels of microbial products including LPS, is associated with risk of mortality, independent of viremia or CD4 T cell loss. This study tested the hypothesis that activation of protein phosphatases by NFV would reduce activation of monocytes/macrophages through dephosphorylation of signal transduction proteins. NFV uniquely blocked LPS-induced production by human monocyte-derived macrophages of the inflammatory cytokines TNF and IL-6, as well as sCD14. Although NFV failed to modulate NF-κB, NFV treatment reduced phosphorylation of AKT and MAPKs. Inhibition of PP2 with okadaic acid blocked the anti-inflammatory effect of NFV, whereas the PP1 inhibitor calyculin A failed to counter the anti-inflammatory effects of NFV. For in vivo studies, plasma sCD14 and LPS were monitored in a cohort of 31 pediatric HIV-1 patients for over 2 years of therapy. Therapy, including NFV, reduced sCD14 levels significantly compared with IDV or RTV, independent of ΔLPS levels, VL, CD4 T cell frequency, or age. The hypothesis was supported as NFV induced activation of PP2 in macrophages, resulting in disruption of inflammatory cell signaling pathways. In vivo evidence supports that NFV may offer beneficial effects independent of antiviral activity by reducing severity of chronic innate immune activation in HIV-1 infection.
Identification of Leading Safety Indicators in Onshore Oil Drilling
Authors: Jablonowski Christopher J.
Published: July 2012

“Leading safety indicators” are variables that are known to correlate with lagging indicators such as accidents. When a leading indicator suggests that the risk of a safety incident is increasing, the safety manager can intervene and mitigate the risk. This paper presents the results of a recently completed study of leading indicators using a data set from an onshore oil and gas drilling operation. This research leverages the results of two previous studies on the same data set to identify leading indicators and to provide guidance regarding intervention. This case study is intended to demonstrate how a quantitative approach can provide specific guidance to safety managers regarding safety policy and decision-making.
Impact of Reservoir Heterogeneity on Steam Assisted Gravity Drainage in Heavy Oil Fractured Reservoirs
Authors: Ali Fattahi , Hamed Akhondzadeh , Nawi Derahman Mohd , Hussin Yunan Mat , Soheil Namazi
Published: July 2012

Despite successful experiences of Steam Assisted Gravity Drainage (SAGD) in sandstone and some studies of this process in fractured reservoirs, the impact of heterogeneity and its relative solutions have not been assessed yet. In this paper, SAGD in fractured reservoirs was studied and the impact of reservoir heterogeneity of fracture permeability, fracture spacing and matrix permeability and solutions to overcome negative impacts were investigated. In contrast to sandstone, it is found that due to the drainage of fracture initial mobile water, steam is injected into reservoir in large amount in early time resulting in fast rising of steam while the lateral expansion of steam is not considerable. Higher fracture permeability at top part of the reservoir showed lower oil recovery than the reversed condition. The impacts of matrix permeability and fracture spacing were combined and expressed in a term Hm/Km (Hm: matrix height, Km: matrix permeability). It was observed that higher value of this term for the top part of the reservoir deteriorates oil recovery more than the reversed condition. The negative impact of heterogeneity can be overcome by locating injector in more fracture permeable zone or the layer having lower quantity of the mentioned term.
Producing Electrical Power in Addition of Heat in Natural Gas Pressure Drop Stations by ICE
Authors: Farzaneh-Gord Mahmood , Khatib Mohsen , Deymi-Dashtebayaz Mahdi , Shahmardan Mohsen
Published: July 2012

Natural gas (NG) must be preheated before pressure reduction takes places at City Gate Stations (CGS). It ensures that gas remains above the hydrate-formation zone and dew point, so no pipeline blockage occurs. The preheating consumes a considerable amount of NG as fuel. In order to operate the CGS more efficiently, a new idea is proposed in this study. The idea is to utilize a Combined Heat and Power (CHP) system in which an Internal Combustion Engine (ICE) acts as a prime mover. The ICE is driving a generator in addition of providing heat for preheating NG. To show the advantage of the proposed system, Mashhad CGS has been chosen as a case study. Results show that a CHP system with two 2.8 MW ICEs is the most appropriate system. The system has the minimum fuel consumption and payback period. Based on the Iranian natural gas consumption of 377 × 106 (m3/day) and by assuming the similar conditions for the other CGSs in Iran, the total amount of extractable electrical power from the CHP systems is predicted to be nearly 91.5 MW. That is equivalent to 802.14 GW.hr/year in 2010 with a yearly benefit about 45 million dollars. According to average annual growing rate of 2.4% of gas consumption in Iran, the predictions are performed until 2035.
Petroleum Systems of the Hebaochang Gas Field in the Southern of Sichuan Basin, SW China
Authors: Gao Pengpeng , Sun Wei , Zhang Lixia , Hu Shuangquan , Zhu Guanfang
Published: July 2012

The Hebaochang gas field is located in the Upper Triassic Xujiahe terrestrial formation of southern Sichuan Basin in China, with at least 374 billion cubic feet (tcf) of proved gas reserves. Because of long-term compression, the reservoirs become mostly tight reservoir with low porosity, low permeability and strong heterogeneity. Furthermore, the contact between gas and water is so complex that there is no uniform gas-water interface. It is unclear for the distribution and physical properties of gas reservoirs and for matching relations between reservoir digenetic evolution and porosity, which hinder the exploration of Xujiahe formation. In this paper, petroleum system has been studied to investigate petroleum accumulation condition and pattern. The conclusions are as follows: (1) The rocks are mainly ash grey-debris-quartz sandstone, ash grey-debris-feldspar quartz sandstone and few feldspar-debris quartz sandstone. The reservoir spaces are mainly remainder intergranular pore and secondary dissolved pore, and it belongs to small pore-thin throat type; (2) Excellent hydrocarbon sources are mainly mudstones and shales from member 1st, member 3rd and member 5th in the Upper Triassic Xujiahe formation. The organic matters mainly consist of I and III types, which are in the late stage of mature to the earlier stage of high mature, so the potential of gas-generation is strong; (3) Reservoirs in member 2nd, member 4th and member 6th of Xujiahe formation produce gas and a little condensate. It is identified that gases mainly come from its coal hydrocarbon source rock and the genesis of natural gas is humus type; (4) Mudstone beds in Jurassic formation are considered as the direct seal for the gas accumulation in Upper Trassic, and the thick mudstones in member 1st, member 3rd and member 5th of Xujiahe formation also as an indirect cap rocks for the reservoir in member 2nd, member 4th and member 6th of Xujiahe formation; (5) Physical property of Xujiahe formation shows that reservoir is so tight that the resistance of natural gas secondary migration is strong, and the buoyancy force is so weak that the driving force of migration is mainly gas expansion. Accumulation pattern of Hebaochang gas field is “near-source gas accumulation-forming model.”
Factors Influencing Coal Bed Methane Reservoir in Southeastern Edge of Ordos Basin, China
Authors: Ding Shuli , Liu Jiajie , Xu Bohui
Published: July 2012

The southeastern edge of Ordos Basin is rich in coal bed methane (CBM) resource (more than 30.8 × 109 m3). The study indicates that rank of coal, maceral composition, depositional environment, thermal evolution history and hydrodynamic are the mainly factors influencing CBM reservoir characterization. The coals in the research area are high rank (1.7% ∼2.4% Ro) vitrinite-rich coals, which is favorable for methane sorption capacity. The peak gas generation occurred form Jurassic to Early Cretaceous period when the Permo-Pennsylvanian coals were deeply buried (about 3500 m) and were subjected to temperatures >160°C. At northeastern part of study area, the coal seam is exposed at the surface and this leads to CBM desorption as lower reservoir pressure. In the meantime, strong groundwater runoff also intensifies CBM loss. There are two patterns of hydrogeological characteristics of coal bed methane-controlled in study area, that is, the hydraulic migration-escape (shallow area in the east) and the hydraulic jam-up (deep area in the west). The former leads to the coal bed methane escape and is unfavorable for accumulation, conversely, the hydraulic jam-up process are favorable for coal bed methane accumulation.
The Properties and Porous Structures of Sulphur-Containing Copolymers
Authors: Podkościelna Beata
Published: July 2012

The copolymerization of two pairs of tetra-functional monomers, viz. bis[4(2-hydroxy-3-acryloyloxypropoxy)phenyl] sulphide with divinylbenzene and bis[4(2-hydroxy-3-methacryloyloxypropoxy)phenyl] sulphide with glycidyl methacrylate, was used for the synthesis of highly cross-linked porous microspheres in the presence of the pore-forming diluents, decan-1-ol and toluene. The porous structures of the obtained microspheres in the dry state (from nitrogen adsorption/desorption measurements) and the swollen state (via inverse size exclusion chromatography) were investigated and compared with those of the bis[4(2-hydroxy-3-methacryloyloxypropoxy)phenyl] sulphide and divinylbenzene copolymers studied previously. The swelling properties of the obtained copolymers as well as their thermal properties as studied by DSC and TG analyses were discussed in detail. The texture of the obtained microspheres was visualized by AFM analysis.
Clarification of Aqueous Stevia Extract Using Alginate Beads — Evaluation by Factorial Design Methodology
Authors: Arakawa Flávia S. , Mahl Cynthia R.A. , de Oliveira Sílvia P.D. , da Igreja Gabriela , Simões Márcia R. , da Silva Classius F.
Published: July 2012

Stevia is used as a sweetener due to its low calorific value and its taste, which is very similar to that of sucrose. Stevia extract is dark in colour and needs to be clarified for better acceptance by consumers. The adsorption processes widely used in clarification do not use organic solvents. Alginate beads have been used as the adsorbent material in the present work. Experiments were carried out in batch mode in which the aqueous stevia extract was mixed with the alginate beads prepared previously by ionotropic gelation. A factorial design was used to study the process of clarification, in which colour removal and the percentage of stevioside adsorbed were evaluated. The studied factors were temperature, pH of the aqueous stevia extract and adsorption time. The results showed that alginate beads are capable of adsorbing both the steviosides and the pigments that give colour to the extract. The experimental design showed that only the pH and contact time were important variables in determining the percentage clarification, in contrast to the other responses which were not affected by the various factors studied. An equation describing the percentage clarification as a function of pH and time is proposed.
Removal of a Basic Dye from Aqueous Solution by a Natural Kaolinitic Clay — Adsorption and Kinetic Studies
Authors: Ganguli Jatindra Nath , Agarwal Sangeeta
Published: July 2012

The < 25 μm fraction of natural clay containing kaolinite, chlorite, illite and illite/smectite mixed layered clay minerals was characterized and used as a potential adsorbent for the removal of Rhodamine B (RB) dye from aqueous solution. Adsorption experiments were carried out in batch mode by varying the following parameters: pH, temperature, initial dye concentration, adsorbent dosage and time of contact. The equilibrium data were well fitted by both the Langmuir and Freundlich adsorption isotherms. The Langmuir monolayer adsorption capacity was found to be 4.77 mg/g, which was better than the value reported for kaolinite (1.95 mg/g). The adsorption process followed pseudo-second-order kinetics. Negative ΔG0 values indicated that adsorption onto this clay was a spontaneous process. A maximum dye uptake of > 90% was achieved at 313 K employing an initial dye concentration of 4.8 × 10−6 M, a pH value of 2 and an adsorbent dosage of 1 g/ℓ.