bluuebunny/crossref_metadata_2025 huggingface dataset:
Implementation research evidence uptake and use for policy-making
Authors: Panisset Ulysses , Koehlmoos Tracey Pérez , Alkhatib Ahmad Hamdi , Pantoja Tomás , Singh Prabal , Kengey-Kayondo Jane , McCutchen Ben , Miguel González Block Ángel
Published: July 2012

A major obstacle to the progress of the Millennium Development Goals has been the inability of health systems in many low- and middle-income countries to effectively implement evidence-informed interventions. This article discusses the relationships between implementation research and knowledge translation and identifies the role of implementation research in the design and execution of evidence-informed policy. After a discussion of the benefits and synergies needed to translate implementation research into action, the article discusses how implementation research can be used along the entire continuum of the use of evidence to inform policy. It provides specific examples of the use of implementation research in national level programmes by looking at the scale up of zinc for the treatment of childhood diarrhoea in Bangladesh and the scaling up of malaria treatment in Burkina Faso. A number of tested strategies to support the transfer of implementation research results into policy-making are provided to help meet the standards that are increasingly expected from evidence-informed policy-making practices.
High expression of high mobility group box 1 (hmgb1) predicts poor prognosis for hepatocellular carcinoma after curative hepatectomy
Authors: Liu Furong , Zhang Yaojun , Peng Zhenwei , Gao Hengjun , Xu Li , Chen Minshan
Published: July 2012

Background

High mobility group box 1(HMGB1) overexpression has been reported in a variety of human cancers. However, the role of HMGB1 in hepatocellular carcinoma (HCC) remains unclear. The aim of present study was to analyze HMGB1 protein expression in tumor, para-tumor and normal tissue and to assess its prognostic significance for HCC after curative hepatectomy.

Methods

The levels of HMGB1 mRNA and protein in tumor, para-tumor and normal tissue were evaluated in 11 HCC cases by Reverse Transcription-polymerase chain reaction (RT-PCR) and Western blot. Additionally, HMGB1 protein expression in 161 HCC was analyzed by immunohistochemistry and correlated with clinicopathological characteristics and survivals. Student’s t-test, spearman’s rank correlation, Kaplan-Meier plots and Cox proportional hazards regression model were used to analyze the data.

Results

By RT-PCR and Western blot, the levels of HMGB1 mRNA and protein were significantly higher in HCC, compared to that in para-tumor (p < 0.001) and normal tissue (p < 0.001). Immunohistochemical staining revealed that high expression of HMGB1 was detected in 42.9% (69/161) HCC cases. High expression of HMGB1 was significantly associated with incomplete encapsulation (p = 0.035) and advanced TNM stage (p = 0.036). Multivariate analysis showed that high expression of HMGB1 was an independent prognostic factor for both overall (p = 0.009, HR = 1.834, 95%CI: 1.167-2.881) and disease-free survival (p = 0.018, HR = 1.622, 95%CI: 1.088-2.419), along with tumor size. Subgroup analysis revealed that high expression of HMGB1 predicted poorer overall survival only for tumor >5 cm (p = 0.031), but not for tumor ≤5 cm (p = 0.101).

Conclusions

HMGB1 protein might contribute to the malignant progression of HCC, high expression of HMGB1 predicts poor prognosis for patients with HCC after curative hepatectomy, especially for patients with tumor >5 cm.
A systematic review and meta-analysis of 235delC mutation of GJB2 gene
Authors: Yao Jun , Lu Yajie , Wei Qinjun , Cao Xin , Xing Guangqian
Published: July 2012

Background

The 235delC mutation of GJB2 gene is considered as a risk factor for the non-syndromic hearing loss (NSHL), and a significant difference in the frequency and distribution of the 235delC mutation has been described world widely.

Methods

A systematic review was performed by means of a meta-analysis to evaluate the influence of the 235delC mutation on the risk of NSHL. A literature search in electronic databases using keywords “235delC”, “GJB2” associated with “carrier frequency” was conducted to include all papers from January 1999 to June 2011. A total of 36 papers were included and there contained 13217 cases and 6521 controls derived from Oceania, American, Europe and Asian.

Results

A remarkable heterogeneity between these studies was observed. The combined results of meta-analysis showed that the 235delC mutant increased the risk of NSHL (OR = 7.9, 95%CI 4.77 ~ 13.11, P <0.00001). Meanwhile, heterogeneity of genetic effect was also observed due to the ethnic specificity and regional disparity. Therefore, the stratified meta-analysis was subsequently conducted and the results indicated that the 235delC mutation was significantly correlated with the risk of NHSL in the East Asian and South-east Asian populations (OR = 12.05, 95%CI 8.33~17.44, P <0.00001), but not significantly in the Oceania and European populations (OR = 10.36, 95%CI: 4.68~22.96, Z = 1.68, P >0.05).

Conclusions

The 235delC mutation of GJB2 gene increased the risk of NHSL in the East Asian and South-east Asian populations, but non-significantly associated with the NSHL susceptibility in Oceania and European populations, suggesting a significant ethnic specificity of this NSHL-associated mutation.
Surface enhanced fluorescence of anti-tumoral drug emodin adsorbed on silver nanoparticles and loaded on porous silicon
Authors: Hernandez Margarita , Recio Gonzalo , Martin-Palma Raul J , Garcia-Ramos Jose V , Domingo Concepcion , Sevilla Paz
Published: July 2012

Fluorescence spectra of anti-tumoral drug emodin loaded on nanostructured porous silicon have been recorded. The use of colloidal nanoparticles allowed embedding of the drug without previous porous silicon functionalization and leads to the observation of an enhancement of fluorescence of the drug. Mean pore size of porous silicon matrices was 60 nm, while silver nanoparticles mean diameter was 50 nm. Atmospheric and vacuum conditions at room temperature were used to infiltrate emodin-silver nanoparticles complexes into porous silicon matrices. The drug was loaded after adsorption on metal surface, alone, and bound to bovine serum albumin. Methanol and water were used as solvents. Spectra with 1 μm spatial resolution of cross-section of porous silicon layers were recorded to observe the penetration of the drug. A maximum fluorescence enhancement factor of 24 was obtained when protein was loaded bound to albumin, and atmospheric conditions of inclusion were used. A better penetration was obtained using methanol as solvent when comparing with water. Complexes of emodin remain loaded for 30 days after preparation without an apparent degradation of the drug, although a decrease in the enhancement factor is observed. The study reported here constitutes the basis for designing a new drug delivery system with future applications in medicine and pharmacy.
Systemic immune challenges trigger and drive Alzheimer-like neuropathology in mice
Authors: Krstic Dimitrije , Madhusudan Amrita , Doehner Jana , Vogel Prisca , Notter Tina , Imhof Claudine , Manalastas Abigail , Hilfiker Martina , Pfister Sandra , Schwerdel Cornelia , Riether Carsten , Meyer Urs , Knuesel Irene
Published: July 2012

Background

Alzheimer’s disease (AD) is the most prevalent form of age-related dementia, and its effect on society increases exponentially as the population ages. Accumulating evidence suggests that neuroinflammation, mediated by the brain’s innate immune system, contributes to AD neuropathology and exacerbates the course of the disease. However, there is no experimental evidence for a causal link between systemic inflammation or neuroinflammation and the onset of the disease.

Methods

The viral mimic, polyriboinosinic-polyribocytidilic acid (PolyI:C) was used to stimulate the immune system of experimental animals. Wild-type (WT) and transgenic mice were exposed to this cytokine inducer prenatally (gestation day (GD)17) and/or in adulthood. Behavioral, immunological, immunohistochemical, and biochemical analyses of AD-associated neuropathologic changes were performed during aging.

Results

We found that a systemic immune challenge during late gestation predisposes WT mice to develop AD-like neuropathology during the course of aging. They display chronic elevation of inflammatory cytokines, an increase in the levels of hippocampal amyloid precursor protein (APP) and its proteolytic fragments, altered Tau phosphorylation, and mis-sorting to somatodendritic compartments, and significant impairments in working memory in old age. If this prenatal infection is followed by a second immune challenge in adulthood, the phenotype is strongly exacerbated, and mimics AD-like neuropathologic changes. These include deposition of APP and its proteolytic fragments, along with Tau aggregation, microglia activation and reactive gliosis. Whereas Aβ peptides were not significantly enriched in extracellular deposits of double immune-challenged WT mice at 15 months, they dramatically increased in age-matched immune-challenged transgenic AD mice, precisely around the inflammation-induced accumulations of APP and its proteolytic fragments, in striking similarity to the post-mortem findings in human patients with AD.

Conclusion

Chronic inflammatory conditions induce age-associated development of an AD-like phenotype in WT mice, including the induction of APP accumulations, which represent a seed for deposition of aggregation-prone peptides. The PolyI:C mouse model therefore provides a unique tool to investigate the molecular mechanisms underlying the earliest pathophysiological changes preceding fibrillary Aβ plaque deposition and neurofibrillary tangle formations in a physiological context of aging. Based on the similarity between the changes in immune-challenged mice and the development of AD in humans, we suggest that systemic infections represent a major risk factor for the development of AD.
Post-ischemic estradiol treatment reduced glial response and triggers distinct cortical and hippocampal signaling in a rat model of cerebral ischemia
Authors: Pérez-Álvarez Maria Jose , Maza Maria del Carmen , Anton Marta , Ordoñez Lara , Wandosell Francisco
Published: July 2012

Background

Estradiol has been shown to exert neuroprotective effects in several neurodegenerative conditions, including cerebral ischemia. The presence of this hormone prior to ischemia attenuates the damage associated with such events in a rodent model (middle cerebral artery occlusion (MCAO)), although its therapeutic value when administered post-ischemia has not been assessed. Hence, we evaluated the effects of estradiol treatment after permanent MCAO (pMCAO) was induced in rats, studying the PI3K/AKT/GSK3/β-catenin survival pathway and the activation of SAPK-JNK in two brain areas differently affected by pMCAO: the cortex and hippocampus. In addition, we analyzed the effect of estradiol on the glial response to injury.

Methods

Male rats were subjected to pMCAO and estradiol (0.04 mg/kg) was administered 6, 24, and 48 h after surgery. The animals were sacrificed 6 h after the last treatment, and brain damage was evaluated by immunohistochemical quantification of ‘reactive gliosis’ using antibodies against GFAP and Iba1. In addition, Akt, phospho-AktSer473, phospho-AktThr308, GSK3, phospho-GSK3Ser21/9, β-catenin, SAPK-JNK, and pSAPK-JNKThr183/Tyr185 levels were determined in western blots of the ipsilateral cerebral cortex and hippocampus, and regional differences in neuronal phospho-Akt expression were determined by immunohistochemistry.

Results

The increases in the percentage of GFAP- (5.25-fold) and Iba1- (1.8-fold) labeled cells in the cortex and hippocampus indicate that pMCAO induced ‘reactive gliosis’. This effect was prevented by post-ischemic estradiol treatment; diminished the number of these cells to those comparable with control animals. pMCAO down-regulated the PI3K/AkT/GSK3/β-catenin survival pathway to different extents in the cortex and hippocampus, the activity of which was restored by estradiol treatment more efficiently in the cerebral cortex (the most affected region) than in the hippocampus. No changes in the phosphorylation of SAPK-JNK were observed 54 h after inducing pMCAO, whereas pMCAO did significantly decrease the phospho-AktSer473 in neurons, an effect that was reversed by estradiol.

Conclusion

The present study demonstrates that post-pMCAO estradiol treatment attenuates ischemic injury in both neurons and glia, events in which the PI3K/AKT/GSK3/β-catenin pathway is at least partly involved. These findings indicate that estradiol is a potentially useful treatment to enhance recovery after human ischemic stroke.
Assessment of renal volume by three-dimensional ultrasonography in pregnant bitches: an experimental study using virtual organ computer-aided analysis
Authors: Mendonça Débora Sartori , Moron Rafael Fontoura Fernandes , Maldonado André Luiz Louzada , Araujo Edward , Nardozza Luciano Marcondes Machado , Moron Antonio Fernandes
Published: July 2012

Background

To assess and to compare the renal volume evolution in bitches during pregnancy by two-dimensional (2D) ultrasonography using the ellipsoid technique (volume = length x width x depth x 0.523) and three-dimensional (3D) ultrasonography using the Virtual Organ Computer-aided AnaLysis (VOCAL) method. A longitudinal prospective study was performed with 17 normal Golden Retrievers bitches during pregnancy from heat to the last third of gestation. The ultrasound scans were performed by two veterinarians. The left and right kidneys were assessed in three moments (day 0 = non-pregnant bitches; days 1st to 20th of pregnancy and days 21st to 40th of pregnancy) by three techniques (ellipsoid; VOCAL 12° and VOCAL 30°). For reproducibility calculations, we used the intraclass correlation coefficient (ICC).

Results

The inferential result of the volumes in ANOVA revealed the interaction effect between side and moment (p = 0.009). The 3D techniques showed, in average, the same renal volumes (p = 0.137) regardless of the side and moment. Considering the right side, the renal volume in the day 0 was smaller than the day 21st to 40th (p = 0.029). Considering the left side, the renal volume at day 0 was smaller than the day 1st to 20th (p = 0.020) and day 21st to 40th (p = 0.007). It was found good intra observer reproducibility (ICC > 0.9) and none of the three techniques showed a good inter observer reproducibility (ICC < 0.7).

Conclusion

The renal volume bitches by 3D ultrasonography using the VOCAL method (12° and 30°) had good correlation with the volume obtained by 2D ultrasonography method.
Rare early prosthesis obstruction after mitral valve replacement: a case report and literature review
Authors: Shi Jun , Bai Zhi-xuan , Hu Jia , Zhang Ben-gui , Guo Ying-qiang
Published: July 2012

As a dreadful complication after the mechanical heart valve replacement, prosthetic valve obstruction caused by pannus formation occurs increasingly with time. The authors here present a case of 42-year-old woman who was urgently admitted to hospital with acute heart failure symptoms due to the mechanical mitral valve failure only 3 months after surgery. Transthoracic and transesophageal echocardiography demonstrated that the bileaflet of the mitral prosthesis were completely immobilized with only a small transvalvular jet remained. During the reoperation, the reason of the prosthetic valve obstruction was attributed to the noncircular pannus ingrowth extending from the atrioventricular side. For a better understanding of the prosthetic valve dysfunction caused by pannus formation, the authors then compile a literature review to briefly discuss the status quo of the clinical characteristics of this uncommon complication.
The atypical homeoprotein Pbx1a participates in the axonal pathfinding of mesencephalic dopaminergic neurons
Authors: Sgadò Paola , Ferretti Elisabetta , Grbec Daniel , Bozzi Yuri , Simon Horst H
Published: July 2012

Background

The pre B-cell leukemia transcription factor 1 (Pbx1) genes belong to the three amino acid loop extension family of homeodomain proteins that form hetero-oligomeric complexes with other homeodomain transcription factors, thereby modulating target specificity, DNA binding affinity and transcriptional activity of their molecular associates.

Results

Here, we provide evidence that Pbx1 is expressed in mesencephalic dopaminergic neurons from embryonic day 11 into adulthood and determines some of the cellular properties of this neuronal population. In Pbx1-deficient mice, the mesencephalic dopaminergic axons stall during mid-gestation at the border between di- and telencephalon before entering the ganglionic eminence, leading to a loose organization of the axonal bundle and partial misrouting. In Pbx1-deficient dopaminergic neurons, the high affinity netrin-1 receptor, deleted in colon cancer (DCC), is down-regulated. Interestingly, we found several conserved Pbx1 binding sites in the first intron of DCC, suggesting a direct regulation of DCC transcription by Pbx1.

Conclusions

The expression of Pbx1 in dopaminergic neurons and its regulation of DCC expression make it an important player in defining the axonal guidance of the midbrain dopaminergic neurons, with possible implications for the normal physiology of the nigro-striatal system as well as processes related to the degeneration of neurons during the course of Parkinson’s disease.
Dynamic optimization of distributed biological systems using robust and efficient numerical techniques
Authors: Vilas Carlos , Balsa-Canto Eva , García Maria-Sonia G , Banga Julio R , Alonso Antonio A
Published: July 2012

Background

Systems biology allows the analysis of biological systems behavior under different conditions through in silico experimentation. The possibility of perturbing biological systems in different manners calls for the design of perturbations to achieve particular goals. Examples would include, the design of a chemical stimulation to maximize the amplitude of a given cellular signal or to achieve a desired pattern in pattern formation systems, etc. Such design problems can be mathematically formulated as dynamic optimization problems which are particularly challenging when the system is described by partial differential equations.

This work addresses the numerical solution of such dynamic optimization problems for spatially distributed biological systems. The usual nonlinear and large scale nature of the mathematical models related to this class of systems and the presence of constraints on the optimization problems, impose a number of difficulties, such as the presence of suboptimal solutions, which call for robust and efficient numerical techniques.

Results

Here, the use of a control vector parameterization approach combined with efficient and robust hybrid global optimization methods and a reduced order model methodology is proposed. The capabilities of this strategy are illustrated considering the solution of a two challenging problems: bacterial chemotaxis and the FitzHugh-Nagumo model.

Conclusions

In the process of chemotaxis the objective was to efficiently compute the time-varying optimal concentration of chemotractant in one of the spatial boundaries in order to achieve predefined cell distribution profiles. Results are in agreement with those previously published in the literature. The FitzHugh-Nagumo problem is also efficiently solved and it illustrates very well how dynamic optimization may be used to force a system to evolve from an undesired to a desired pattern with a reduced number of actuators. The presented methodology can be used for the efficient dynamic optimization of generic distributed biological systems.
Rational drug repositioning guided by an integrated pharmacological network of protein, disease and drug
Authors: Lee Hee Sook , Bae Taejeong , Lee Ji-Hyun , Kim Dae Gyu , Oh Young Sun , Jang Yeongjun , Kim Ji-Tea , Lee Jong-Jun , Innocenti Alessio , Supuran Claudiu T , Chen Luonan , Rho Kyoohyoung , Kim Sunghoon
Published: July 2012

Background

The process of drug discovery and development is time-consuming and costly, and the probability of success is low. Therefore, there is rising interest in repositioning existing drugs for new medical indications. When successful, this process reduces the risk of failure and costs associated with de novo drug development. However, in many cases, new indications of existing drugs have been found serendipitously. Thus there is a clear need for establishment of rational methods for drug repositioning.

Results

In this study, we have established a database we call “PharmDB” which integrates data associated with disease indications, drug development, and associated proteins, and known interactions extracted from various established databases. To explore linkages of known drugs to diseases of interest from within PharmDB, we designed the Shared Neighborhood Scoring (SNS) algorithm. And to facilitate exploration of tripartite (Drug-Protein-Disease) network, we developed a graphical data visualization software program called phExplorer, which allows us to browse PharmDB data in an interactive and dynamic manner. We validated this knowledge-based tool kit, by identifying a potential application of a hypertension drug, benzthiazide (TBZT), to induce lung cancer cell death.

Conclusions

By combining PharmDB, an integrated tripartite database, with Shared Neighborhood Scoring (SNS) algorithm, we developed a knowledge platform to rationally identify new indications for known FDA approved drugs, which can be customized to specific projects using manual curation. The data in PharmDB is open access and can be easily explored with phExplorer and accessed via BioMart web service (http://www.i-pharm.org/, http://biomart.i-pharm.org/).
Dapson in heterocyclic chemistry, part VIII: synthesis, molecular docking and anticancer activity of some novel sulfonylbiscompounds carrying biologically active 1,3-dihydropyridine, chromene and chromenopyridine moieties
Authors: Al-Said Mansour S , Ghorab Mostafa M , Nissan Yassin M
Published: July 2012

Several new sulfonebiscompounds having a biologically active 1,2-dihydropyridine-2-one 3–19, acrylamide 20, chromene 21, 22 and chromenopyridine 23, 24 moieties were synthesized and evaluated as potential anticancer agents. The structures of the products were confirmed via elemental analyses and spectral data. The screening tests showed that many of the biscompounds obtained exhibited good anticancer activity against human breast cell line (MCF7) comparable to doxorubicin which was used as reference drug. Compounds 11, 17 and 24 showed IC50 values 35.40 μM, 29.86 μM and 30.99 μM, respectively. In order to elucidate the mechanism of action of the synthesized compounds as anticancer agents, docking on the active site of farnesyltransferase and arginine methyltransferase was also performed and good results were obtained.
Novel enzymes for the degradation of cellulose
Authors: Horn Svein Jarle , Vaaje-Kolstad Gustav , Westereng Bjørge , Eijsink VincentGH
Published: July 2012

The bulk terrestrial biomass resource in a future bio-economy will be lignocellulosic biomass, which is recalcitrant and challenging to process. Enzymatic conversion of polysaccharides in the lignocellulosic biomass will be a key technology in future biorefineries and this technology is currently the subject of intensive research. We describe recent developments in enzyme technology for conversion of cellulose, the most abundant, homogeneous and recalcitrant polysaccharide in lignocellulosic biomass. In particular, we focus on a recently discovered new type of enzymes currently classified as CBM33 and GH61 that catalyze oxidative cleavage of polysaccharides. These enzymes promote the efficiency of classical hydrolytic enzymes (cellulases) by acting on the surfaces of the insoluble substrate, where they introduce chain breaks in the polysaccharide chains, without the need of first “extracting” these chains from their crystalline matrix.
AdapterRemoval: easy cleaning of next-generation sequencing reads
Authors: Lindgreen Stinus
Published: July 2012

Background

With the advent of next-generation sequencing there is an increased demand for tools to pre-process and handle the vast amounts of data generated. One recurring problem is adapter contamination in the reads, i.e. the partial or complete sequencing of adapter sequences. These adapter sequences have to be removed as they can hinder correct mapping of the reads and influence SNP calling and other downstream analyses.

Findings

We present a tool called AdapterRemoval which is able to pre-process both single and paired-end data. The program locates and removes adapter residues from the reads, it is able to combine paired reads if they overlap, and it can optionally trim low-quality nucleotides. Furthermore, it can look for adapter sequence in both the 5’ and 3’ ends of the reads. This is a flexible tool that can be tuned to accommodate different experimental settings and sequencing platforms producing FASTQ files. AdapterRemoval is shown to be good at trimming adapters from both single-end and paired-end data.

Conclusions

AdapterRemoval is a comprehensive tool for analyzing next-generation sequencing data. It exhibits good performance both in terms of sensitivity and specificity. AdapterRemoval has already been used in various large projects and it is possible to extend it further to accommodate application-specific biases in the data.
Rehospitalization following percutaneous coronary intervention for commercially insured patients with acute coronary syndrome: a retrospective analysis
Authors: Meadows Eric S , Bae Jay P , Zagar Anthony , Sugihara Tomoko , Ramaswamy Krishnan , McCracken Rebecca , Heiselman Darell
Published: July 2012

Background

While prior research has provided important information about readmission rates following percutaneous coronary intervention, reports regarding charges and length of stay for readmission beyond 30 days post-discharge for patients in a large cohort are limited. The objective of this study was to characterize the rehospitalization of patients with acute coronary syndrome receiving percutaneous coronary intervention in a U.S. health benefit plan.

Methods

This study retrospectively analyzed administrative claims data from a large US managed care plan at index hospitalization, 30-days, and 31-days to 15-months rehospitalization. A valid Diagnosis Related Group code (version 24) associated with a PCI claim (codes 00.66, 36.0X, 929.73, 929.75, 929.78–929.82, 929.84, 929.95/6, and G0290/1) was required to be included in the study. Patients were also required to have an ACS diagnosis on the day of admission or within 30 days prior to the index PCI. ACS diagnoses were classified by the International Statistical Classification of Disease 9 (ICD-9-CM) codes 410.xx or 411.11. Patients with a history of transient ischemic attack or stroke were excluded from the study because of the focus only on ACS-PCI patients. A clopidogrel prescription claim was required within 60 days after hospitalization.

Results

Of the 6,687 ACS-PCI patients included in the study, 5,174 (77.4%) were male, 5,587 (83.6%) were <65 years old, 4,821 (72.1%) had hypertension, 5,176 (77.4%) had hyperlipidemia, and 1,777 (26.6%) had diabetes. At index hospitalization drug-eluting stents were the most frequently used: 5,534 (82.8%). Of the 4,384 patients who completed the 15-month follow-up, a total of 1,367 (31.2%) patients were rehospitalized for cardiovascular (CV)-related events, of which 811 (59.3%) were revascularization procedures: 13 (1.0%) for coronary artery bypass graft and 798 (58.4%) for PCI. In general, rehospitalizations associated with revascularization procedures cost more than other CV-related rehospitalizations. Patients rehospitalized for revascularization procedures had the shortest median time from post-index PCI to rehospitalization when compared to the patients who were rehospitalized for other CV-related events.

Conclusions

For ACS patients who underwent PCI, revascularization procedures represented a large portion of rehospitalizations. Revascularization procedures appear to be the most frequent, most costly, and earliest cause for rehospitalization after ACS-PCI.
Challenges to improved therapeutics for metastatic castrate resistant prostate cancer: from recent successes and failures
Authors: Huang Xuan , Chau Cindy H , Figg William D
Published: July 2012

Men with metastatic castration-resistant prostate cancer (mCRPC) carry poor prognosis despite the use of docetaxel-based regimens which has modest survival benefit shown by randomized clinical trials. Significant progress in the discovery of novel therapeutic agents has been made in the past few years. While sipuleucel-T, cabazitaxel, and abiraterone gained regulatory approval in 2010 and 2011, several highly promising candidates/regimens have failed in large scale clinical trials. Challenges remain to optimize the design and interpretation of clinical trial results and develop more effective strategies for mCRPC. In this review, we examined the positive and negative clinical trials in mCRPC in the past and discussed the various aspects of clinical trial design including selection of targets and appropriate outcome measures, biomarker development and implementation, and strategies for combination therapy.
Effect of phenylhexyl isothiocyanate on aberrant histone H3 methylation in primary human acute leukemia
Authors: Zou Yong , Ma Xudong , Huang Yiqun , Hong Lingling , Chiao Jen-wei
Published: July 2012

Background

We have previously studied the histone acetylation in primary human leukemia cells. However, histone H3 methylation in these cells has not been characterized.

Methods

This study examined the methylation status at histone H3 lysine 4 (H3K4) and histone H3 lysine 9 (H3K9) in primary acute leukemia cells obtained from patients and compared with those in the non-leukemia and healthy cells. We further characterized the effect of phenylhexyl isothiocyanate (PHI), Trichostatin A (TSA), and 5-aza-2’-deoxycytidine (5-Aza) on the cells.

Results

We found that methylation of histone H3K4 was virtually undetectable, while methylation at H3K9 was significantly higher in primary human leukemia cells. The histone H3K9 hypermethylation and histone H3K4 hypomethylation were observed in both myeloid and lymphoid leukemia cells. PHI was found to be able to normalize the methylation level in the primary leukemia cells. We further showed that PHI was able to enhance the methyltransferase activity of H3K4 and decrease the activity of H3K9 methyltransferase. 5-Aza had similar effect on H3K4, but minimal effect on H3K9, whereas TSA had no effect on H3K4 and H3K9 methyltransferases.

Conclusions

This study revealed opposite methylation level of H3K4 and H3K9 in primary human leukemia cells and demonstrated for the first time that PHI has different effects on the methyltransferases for H3K4 and H3K9.
Morphology of ovaries in laron dwarf mice, with low circulating plasma levels of insulin-like growth factor-1 (IGF-1), and in bovine GH-transgenic mice, with high circulating plasma levels of IGF-1
Authors: Słuczanowska-Głąbowska Sylwia , Laszczyńska Maria , Piotrowska Katarzyna , Głąbowski Wojciech , Kopchick John J , Bartke Andrzej , Kucia Magda , Ratajczak Mariusz Z
Published: July 2012

Background

It is well known that somatotrophic/insulin signaling affects lifespan in experimental animals, and one of the signs of aging is progressive gonadal dysfunction.

Methods

To study the effects of insulin-like growth factor-1 (IGF-1) plasma level on ovaries, we analyzed ovaries isolated from 2-year-old growth hormone receptor knockout (GHR-KO) Laron dwarf mice, with low circulating plasma levels of IGF-1, and 6-month-old bovine growth hormone transgenic (bGHTg) mice, with high circulating plasma levels of IGF-1. The ages of the Laron dwarf mutants employed in our studies were selected based on their overall survival (up to ~ 4 years for Laron dwarf mice and ~ 1 year for bGHTg mice).

Results

Morphological analysis of the ovaries of mice that reached ~50% of their maximal life span revealed a lower biological age for the ovaries isolated from 2-year-old Laron dwarf mice than their normal-lifespan wild type littermates. By contrast, the ovarian morphology of increased in size 6 month old bGHTg mice was generally normal.

Conclusion

Ovaries isolated from 2-year-old Laron dwarf mice exhibit a lower biological age compared with ovaries from normal WT littermates at the same age. At the same time, no morphological features of accelerated aging were found in 0.5-year-old bGHTg mice compared with ovaries from normal the same age-matched WT littermates.
Modifying effect of gender on the prognostic value of clinicopathological factors and Ki67 expression in melanoma: a population-based cohort study
Authors: Fridberg Marie , Jonsson Liv , Bergman Julia , Nodin Björn , Jirström Karin
Published: July 2012

Background

Malignant melanoma is the most deadly form of skin cancer. Female sex is known to have a protective effect on incidence, tumour characteristics, and mortality from melanoma. However, the potentially modifying effect of sex on the prognostic significance of clinicopathological and investigative factors is generally not taken into consideration in biomarker studies. In this study, we compared the sex-specific distribution and prognostic value of established tumour characteristics and Ki67 expression in 255 cases of incident primary melanoma in a prospective, population-based cohort study.

Methods

The study included 255 incident cases of melanoma, 132 females and 123 males, in the Malmö Diet and Cancer Study. Tumours from 226 (88.6%) cases had been assembled in tissue microarrays. Clinicopathological factors and immunohistochemical Ki67 expression were assessed and correlated with disease-free survival (DFS) and overall survival (OS) using Kaplan-Meier analysis, log rank test and univariable and multivariable Cox regression analyses, stratified for gender. Effect of gender on melanoma-specific survival (MSS) after first recurrence was also analysed.

Results

Women were significantly younger at diagnosis than men (p = 0.012). The most common tumour sites were the legs in women (37.5%) and the dorsal trunk in men (37.8%). Kaplan-Meier analysis revealed that tumour location had no prognostic impact in women, but in men, location to the frontal trunk was significantly associated with a reduced DFS compared with all other locations combined and location to the dorsal trunk was significantly associated with a prolonged OS. High Ki67 expression was significantly associated with a reduced DFS and OS in men but not in women, also when adjusted for other factors. In men, but not in women, ulceration was an independent prognostic factor for both DFS and OS. MSS after first local, regional or distant recurrence was significantly shorter for men than for women.

Conclusions

The results from this study demonstrate that the prognostic value of tumour location, Ki67 expression and ulceration in melanoma differs according to gender. These findings need to be validated in future studies, as they may help improve prognostication in patients with melanoma. Moreover, our findings demonstrate that sex-stratified analyses add valuable information to biomarker studies.
Williamson-Hall analysis in estimation of lattice strain in nanometer-sized ZnO particles
Authors: Mote VD , Purushotham Y , Dole BN
Published: July 2012

ZnO nanoparticles were prepared by coprecipitation method at 450C. X-ray diffraction result indicates that the sample is having a crystalline wurtzite phase. Transmission electron microscopy (TEM) result reveals that the ZnO sample is spherical in shape with an average grain size of about 50nm. X-ray peak broadening analysis was used to evaluate the crystalline sizes and lattice strain by the Williamson-Hall (W-H) analysis. All other relevant physical parameters such as strain, stress, and energy density values were also calculated using W-H analysis with different models, viz, uniform deformation model, uniform deformation stress model and uniform deformation energy density model. The root mean square strain was determined from the interplanar spacing and strain estimated from the three models. The three models yield different strain values; it may be due to the anisotropic nature of the material. The mean particle size of ZnO nanoparticles estimated from TEM analysis, Scherrers formula and W-H analysis is highly intercorrelated.
A novel autoantibody against fibronectin leucine-rich transmembrane protein 2 expressed on the endothelial cell surface identified by retroviral vector system in systemic lupus erythematosus
Authors: Shirai Tsuyoshi , Fujii Hiroshi , Ono Masao , Nakamura Kyohei , Watanabe Ryu , Tajima Yumi , Takasawa Naruhiko , Ishii Tomonori , Harigae Hideo
Published: July 2012

Introduction

Anti-endothelial cell antibodies (AECAs) are thought to be critical for vasculitides in collagen diseases, but most were directed against molecules localized within the cell and not expressed on the cell surface. To clarify the pathogenic roles of AECAs, we constructed a retroviral vector system for identification of autoantigens expressed on the endothelial cell surface.

Methods

AECA activity in sera from patients with collagen diseases was measured with flow cytometry by using human umbilical vein endothelial cells (HUVECs). A cDNA library of HUVECs was retrovirally transfected into a rat myeloma cell line, from which AECA-positive clones were sorted with flow cytometry. cDNA of the cells was analyzed to identify an autoantigen, and then the clinical characteristics and the functional significance of the autoantibody were evaluated.

Results

Two distinct AECA-positive clones were isolated by using serum immunoglobulin G (IgG) from a patient with systemic lupus erythematosus (SLE). Both clones were identical to cDNA of fibronectin leucine-rich transmembrane protein 2 (FLRT2). HUVECs expressed FLRT2 and the prototype AECA IgG bound specifically to FLRT2-transfected cells. Anti-FLRT2 antibody activity accounted for 21.4% of AECAs in SLE. Furthermore, anti-FLRT2 antibody induced complement-dependent cytotoxicity against FLRT2-expressing cells.

Conclusions

We identified the membrane protein FLRT2 as a novel autoantigen of AECAs in SLE patients by using the retroviral vector system. Anti-FLRT2 antibody has the potential to induce direct endothelial cell cytotoxicity in about 10% of SLE patients and could be a novel molecular target for intervention. Identification of such a cell-surface target for AECAs may reveal a comprehensive mechanism of vascular injury in collagen diseases.
Lack of transforming growth factor-β signaling promotes collective cancer cell invasion through tumor-stromal crosstalk
Authors: Matise Lauren A , Palmer Trenis D , Ashby William J , Nashabi Abudi , Chytil Anna , Aakre Mary , Pickup Michael W , Gorska Agnieszka E , Zijlstra Andries , Moses Harold L
Published: July 2012

Introduction

Transforming growth factor beta (TGF-β) has a dual role during tumor progression, initially as a suppressor and then as a promoter. Epithelial TGF-β signaling regulates fibroblast recruitment and activation. Concurrently, TGF-β signaling in stromal fibroblasts suppresses tumorigenesis in adjacent epithelia, while its ablation potentiates tumor formation. Much is known about the contribution of TGF-β signaling to tumorigenesis, yet the role of TGF-β in epithelial-stromal migration during tumor progression is poorly understood. We hypothesize that TGF-β is a critical regulator of tumor-stromal interactions that promote mammary tumor cell migration and invasion.

Methods

Fluorescently labeled murine mammary carcinoma cells, isolated from either MMTV-PyVmT transforming growth factor-beta receptor II knockout (TβRII KO) or TβRIIfl/fl control mice, were combined with mammary fibroblasts and xenografted onto the chicken embryo chorioallantoic membrane. These combinatorial xenografts were used as a model to study epithelial-stromal crosstalk. Intravital imaging of migration was monitored ex ovo, and metastasis was investigated in ovo. Epithelial RNA from in ovo tumors was isolated by laser capture microdissection and analyzed to identify gene expression changes in response to TGF-β signaling loss.

Results

Intravital microscopy of xenografts revealed that mammary fibroblasts promoted two migratory phenotypes dependent on epithelial TGF-β signaling: single cell/strand migration or collective migration. At epithelial-stromal boundaries, single cell/strand migration of TβRIIfl/fl carcinoma cells was characterized by expression of α-smooth muscle actin and vimentin, while collective migration of TβRII KO carcinoma cells was identified by E-cadherin+/p120+/β-catenin+ clusters. TβRII KO tumors also exhibited a twofold greater metastasis than TβRIIfl/fl tumors, attributed to enhanced extravasation ability. In TβRII KO tumor epithelium compared with TβRIIfl/fl epithelium, Igfbp4 and Tspan13 expression was upregulated while Col1α2, Bmp7, Gng11, Vcan, Tmeff1, and Dsc2 expression was downregulated. Immunoblotting and quantitative PCR analyses on cultured cells validated these targets and correlated Tmeff1 expression with disease progression of TGF-β-insensitive mammary cancer.

Conclusion

Fibroblast-stimulated carcinoma cells utilize TGF-β signaling to drive single cell/strand migration but migrate collectively in the absence of TGF-β signaling. These migration patterns involve the signaling regulation of several epithelial-to-mesenchymal transition pathways. Our findings concerning TGF-β signaling in epithelial-stromal interactions are important in identifying migratory mechanisms that can be targeted as recourse for breast cancer treatment.
Conserved rules govern genetic interaction degree across species
Authors: Koch Elizabeth N , Costanzo Michael , Bellay Jeremy , Deshpande Raamesh , Chatfield-Reed Kate , Chua Gordon , D'Urso Gennaro , Andrews Brenda J , Boone Charles , Myers Chad L
Published: July 2012

Background

Synthetic genetic interactions have recently been mapped on a genome scale in the budding yeast Saccharomyces cerevisiae, providing a functional view of the central processes of eukaryotic life. Currently, comprehensive genetic interaction networks have not been determined for other species, and we therefore sought to model conserved aspects of genetic interaction networks in order to enable the transfer of knowledge between species.

Results

Using a combination of physiological and evolutionary properties of genes, we built models that successfully predicted the genetic interaction degree of S. cerevisiae genes. Importantly, a model trained on S. cerevisiae gene features and degree also accurately predicted interaction degree in the fission yeast Schizosaccharomyces pombe, suggesting that many of the predictive relationships discovered in S. cerevisiae also hold in this evolutionarily distant yeast. In both species, high single mutant fitness defect, protein disorder, pleiotropy, protein-protein interaction network degree, and low expression variation were significantly predictive of genetic interaction degree. A comparison of the predicted genetic interaction degrees of S. pombe genes to the degrees of S. cerevisiae orthologs revealed functional rewiring of specific biological processes that distinguish these two species. Finally, predicted differences in genetic interaction degree were independently supported by differences in co-expression relationships of the two species.

Conclusions

Our findings show that there are common relationships between gene properties and genetic interaction network topology in two evolutionarily distant species. This conservation allows use of the extensively mapped S. cerevisiae genetic interaction network as an orthology-independent reference to guide the study of more complex species.
Whole-genome sequencing and analysis of the Malaysian cynomolgus macaque (Macaca fascicularis) genome
Authors: Higashino Atsunori , Sakate Ryuichi , Kameoka Yosuke , Takahashi Ichiro , Hirata Makoto , Tanuma Reiko , Masui Tohru , Yasutomi Yasuhiro , Osada Naoki
Published: July 2012

Background

The genetic background of the cynomolgus macaque (Macaca fascicularis) is made complex by the high genetic diversity, population structure, and gene introgression from the closely related rhesus macaque (Macaca mulatta). Herein we report the whole-genome sequence of a Malaysian cynomolgus macaque male with more than 40-fold coverage, which was determined using a resequencing method based on the Indian rhesus macaque genome.

Results

We identified approximately 9.7 million single nucleotide variants (SNVs) between the Malaysian cynomolgus and the Indian rhesus macaque genomes. Compared with humans, a smaller nonsynonymous/synonymous SNV ratio in the cynomolgus macaque suggests more effective removal of slightly deleterious mutations. Comparison of two cynomolgus (Malaysian and Vietnamese) and two rhesus (Indian and Chinese) macaque genomes, including previously published macaque genomes, suggests that Indochinese cynomolgus macaques have been more affected by gene introgression from rhesus macaques. We further identified 60 nonsynonymous SNVs that completely differentiated the cynomolgus and rhesus macaque genomes, and that could be important candidate variants for determining species-specific responses to drugs and pathogens. The demographic inference using the genome sequence data revealed that Malaysian cynomolgus macaques have experienced at least three population bottlenecks.

Conclusions

This list of whole-genome SNVs will be useful for many future applications, such as an array-based genotyping system for macaque individuals. High-quality whole-genome sequencing of the cynomolgus macaque genome may aid studies on finding genetic differences that are responsible for phenotypic diversity in macaques and may help control genetic backgrounds among individuals.
Internet sex addiction: a licence to lust?
Authors: Dunn Nick , Seaburne-May Matthew , Gatter Philip
Published: July 2012

In this article we ask what kind of phenomenon is internet sex addiction. From the perspectives of two practising psychiatrists, one of whom has worked in a weekly sexual disorders clinic for 12 years, and an anthropologist we explore whether a moral panic is emerging over sexual behaviour and the internet, and whether internet sex addiction forms part of any such panic. We ask whether many individuals who diagnose themselves as addicted to internet-based sex do so more out of a media-activated sensibility than a clinical reality. We also consider what developments in DSM-5 hold for this area.
Simulation in psychiatric teaching
Authors: Dave Subodh
Published: July 2012

The use of simulated patients in medicine offers students a standardised learning experience and a reproducible way of exploring attitudes and teaching communication skills. This would seem to be particularly relevant to psychiatry with its focus on attitudes and interpersonal skills, but doubts have been raised about the utility of simulated patients in teaching skills such as empathy and the generalisability of this learning to the real world. This, tempered with cost implications, may have limited the use of simulated patients to assessment through objective structured clinical examinations rather than to teaching and to learning. This article examines the educational advantages and disadvantages of the use of simulated patients in psychiatric teaching and argues that their judicious use complements undergraduate and postgraduate training in psychiatry. The article offers practical tips on writing simulated patient scenarios to deliver specific learning objectives and discusses the potential use of novel simulation techniques in psychiatric education.