bluuebunny/crossref_metadata_2025 huggingface dataset:
RegTransBase – a database of regulatory sequences and interactions based on literature: a resource for investigating transcriptional regulation in prokaryotes
Authors: Cipriano Michael J , Novichkov Pavel N , Kazakov Alexey E , Rodionov Dmitry A , Arkin Adam P , Gelfand Mikhail S , Dubchak Inna
Published: April 2013

Background

Due to the constantly growing number of sequenced microbial genomes, comparative genomics has been playing a major role in the investigation of regulatory interactions in bacteria. Regulon inference mostly remains a field of semi-manual examination since absence of a knowledgebase and informatics platform for automated and systematic investigation restricts opportunities for computational prediction. Additionally, confirming computationally inferred regulons by experimental data is critically important.

Description

RegTransBase is an open-access platform with a user-friendly web interface publicly available at http://regtransbase.lbl.gov. It consists of two databases – a manually collected hierarchical regulatory interactions database based on more than 7000 scientific papers which can serve as a knowledgebase for verification of predictions, and a large set of curated by experts transcription factor binding sites used in regulon inference by a variety of tools. RegTransBase captures the knowledge from published scientific literature using controlled vocabularies and contains various types of experimental data, such as: the activation or repression of transcription by an identified direct regulator; determination of the transcriptional regulatory function of a protein (or RNA) directly binding to DNA or RNA; mapping of binding sites for a regulatory protein; characterization of regulatory mutations. Analysis of the data collected from literature resulted in the creation of Putative Regulons from Experimental Data that are also available in RegTransBase.

Conclusions

RegTransBase is a powerful user-friendly platform for the investigation of regulation in prokaryotes. It uses a collection of validated regulatory sequences that can be easily extracted and used to infer regulatory interactions by comparative genomics techniques thus assisting researchers in the interpretation of transcriptional regulation data.
TRACER: a resource to study the regulatory architecture of the mouse genome
Authors: Chen Chao-Kung , Symmons Orsolya , Uslu Veli Vural , Tsujimura Taro , Ruf Sandra , Smedley Damian , Spitz François
Published: April 2013

Background

Mammalian genes are regulated through the action of multiple regulatory elements, often distributed across large regions. The mechanisms that control the integration of these diverse inputs into specific gene expression patterns are still poorly understood. New approaches enabling the dissection of these mechanisms in vivo are needed.

Results

Here, we describe TRACER (http://tracerdatabase.embl.de), a resource that centralizes information from a large on-going functional exploration of the mouse genome with different transposon-associated regulatory sensors. Hundreds of insertions have been mapped to specific genomic positions, and their corresponding regulatory potential has been documented by analysis of the expression of the reporter sensor gene in mouse embryos. The data can be easily accessed and provides information on the regulatory activities present in a large number of genomic regions, notably in gene-poor intervals that have been associated with human diseases.

Conclusions

TRACER data enables comparisons with the expression pattern of neighbouring genes, activity of surrounding regulatory elements or with other genomic features, revealing the underlying regulatory architecture of these loci. TRACER mouse lines can also be requested for in vivo transposition and chromosomal engineering, to analyse further regions of interest.
Systematic antibody generation and validation via tissue microarray technology leading to identification of a novel protein prognostic panel in breast cancer
Authors: O´Leary Patrick C , Penny Sarah A , Dolan Roisin T , Kelly Catherine M , Madden Stephen F , Rexhepaj Elton , Brennan Donal J , McCann Amanda H , Pontén Fredrik , Uhlén Mathias , Zagozdzon Radoslaw , Duffy Michael J , Kell Malcolm R , Jirström Karin , Gallagher William M
Published: April 2013

Background

Although omic-based discovery approaches can provide powerful tools for biomarker identification, several reservations have been raised regarding the clinical applicability of gene expression studies, such as their prohibitive cost. However, the limited availability of antibodies is a key barrier to the development of a lower cost alternative, namely a discrete collection of immunohistochemistry (IHC)-based biomarkers. The aim of this study was to use a systematic approach to generate and screen affinity-purified, mono-specific antibodies targeting progression-related biomarkers, with a view towards developing a clinically applicable IHC-based prognostic biomarker panel for breast cancer.

Methods

We examined both in-house and publicly available breast cancer DNA microarray datasets relating to invasion and metastasis, thus identifying a cohort of candidate progression-associated biomarkers. Of these, 18 antibodies were released for extended analysis. Validated antibodies were screened against a tissue microarray (TMA) constructed from a cohort of consecutive breast cancer cases (n = 512) to test the immunohistochemical surrogate signature.

Results

Antibody screening revealed 3 candidate prognostic markers: the cell cycle regulator, Anillin (ANLN); the mitogen-activated protein kinase, PDZ-Binding Kinase (PBK); and the estrogen response gene, PDZ-Domain Containing 1 (PDZK1). Increased expression of ANLN and PBK was associated with poor prognosis, whilst increased expression of PDZK1 was associated with good prognosis. A 3-marker signature comprised of high PBK, high ANLN and low PDZK1 expression was associated with decreased recurrence-free survival (p < 0.001) and breast cancer-specific survival (BCSS) (p < 0.001). This novel signature was associated with high tumour grade (p < 0.001), positive nodal status (p = 0.029), ER-negativity (p = 0.006), Her2-positivity (p = 0.036) and high Ki67 status (p < 0.001). However, multivariate Cox regression demonstrated that the signature was not a significant predictor of BCSS (HR = 6.38; 95% CI = 0.79-51.26, p = 0.082).

Conclusions

We have developed a comprehensive biomarker pathway that extends from discovery through to validation on a TMA platform. This proof-of-concept study has resulted in the identification of a novel 3-protein prognostic panel. Additional biochemical markers, interrogated using this high-throughput platform, may further augment the prognostic accuracy of this panel to a point that may allow implementation into routine clinical practice.
Mortality among British Columbians testing for hepatitis C antibody
Authors: Yu Amanda , Spinelli John J , Cook Darrel A , Buxton Jane A , Krajden Mel
Published: April 2013

Background

Hepatitis C virus (HCV) infection is a major preventable and treatable cause of morbidity and mortality. The ability to link population based centralized laboratory HCV testing data with administrative databases provided a unique opportunity to compare mortality between HCV seronegative and seropositive individuals. Through the use of laboratory testing patterns and results, the objective of this study was to differentiate the viral effects of mortality due to HCV infection from risk behaviours/activities that are associated with acquisition of HCV infection.

Methods

Serological testing data from the British Columbia (BC) Centre for Disease Control Public Health Microbiology and Reference Laboratory from 1992–2004 were linked to the BC Vital Statistics Agency death registry. Four groups of HCV testers were defined by their HCV antibody (anti-HCV) testing patterns: single non-reactive (SNR); serial multiple tested non-reactive (MNR); reactive at initial testing (REAC); and seroconverter (SERO) (previously seronegative followed by reactive, a marker for incident infection). Standardized mortality ratios (SMRs) were calculated to compare the relative risk of all cause and disease specific mortality to that of the BC population for each serological group. Time dependent Cox proportional hazard regression was used to compare hazard ratios (HRs) among HCV serological groups.

Results

All anti-HCV testers had higher SMRs than the BC population. Referent to the SNR group, the REAC group had higher risks for liver (HR: 9.62; 95% CI=8.55-10.87) and drug related mortality (HR: 13.70; 95% CI=11.76-16.13). Compared to the REAC group, the SERO group had a lower risk for liver (HR: 0.53; 95% CI=0.24-0.99), but a higher risk for drug related mortality (HR: 1.54; 95% CI=1.12-2.05).

Conclusions

These findings confirm that individuals who test anti-HCV positive have increased mortality related to progressive liver disease, and that a substantial proportion of the mortality is attributable to drug use and risk behaviours/activities associated with HCV acquisition. Mortality reduction in HCV infected individuals will require comprehensive prevention programming to reduce the harms due to behaviours/activities which relate to HCV acquisition, as well as HCV treatment to prevent progression of chronic liver disease.
Dracaena arborea alleviates ultra-structural spermatogenic alterations in streptozotocin-induced diabetic rats
Authors: Wankeu-Nya Modeste , Florea Adrian , Bâlici Stefana , Watcho Pierre , Matei Horea , Kamanyi Albert
Published: April 2013

Background

Infertility is a common complication in diabetic men and experimental animals, mainly due to loss of germ cells by apoptotic cell death. The aim of this study was to evaluate the effects of aqueous and ethanol extracts of Dracaena arborea in streptozotocin-induced ultra-structural spermatogenic alterations in Wistar rats.

Methods

Diabetic animals were orally treated with Millipore water (10 ml/kg), sildenafil citrate (1.44 mg/kg) or Dracaena arborea aqueous (500 mg/kg) and ethanol (100 mg/kg) extracts for three weeks. A group of non diabetic rats received Millipore water (10 ml/kg) and served as healthy control group. Blood glucose was monitored at the beginning and the end of the study. One day after the last treatment, animals were sacrificed and the testes immediately removed were morphologically observed and prepared for electron microscopy analysis of spermatogenesis.

Results

Our results showed that Dracaena arborea was devoid of any anti-hyperglycemic activity. In the untreated diabetic rats, hyperglycemia severely damaged the testes morphology as well as the spermatogenic process as evidenced by the: thickness of basement membrane of the seminiferous tubule; mitochondria alteration; abnormal spermatocyte cells displaying polymorphous nuclei, cytoplasmic vacuolization and necrosis; and disorganization and degeneration of sperm germ cells. Administration of sildenafil citrate and Dracaena arborea extracts to the diabetic rats improved testes morphology and reversed, although not completely, the impairment of spermatogenesis; this alleviating effect was more pronounced in animals treated with the aqueous extract (500 mg/kg) of Dracaena arborea.

Conclusion

Dracaena arborea improves testes morphology and restores spermatogenesis in type 1 diabetic rats, without having major anti-hyperglycemic properties. These effects could be attributed to saponins, flavonoids, phenols and sterols revealed in this plant, which could be a useful component in the treatment of diabetes-induced testicular dysfunction.
Could the Sasang constitution itself be a risk factor of abdominal obesity?
Authors: Jang Eunsu , Baek Younghwa , Park Kihyun , Lee Siwoo
Published: April 2013

Background

Abdominal obesity (AO) is a medical condition in which excess body fat accumulates in the abdomen. It may cause adverse effects on health and result in reduced life expectancy or increased health problems. While various genetic approaches have explained the risks of AO in Western society, the Sasang constitution (SC) has been identified as a risk factor in Korean medicine. Different SC types are associated with different fat distribution, body shapes and susceptibility to diseases. We evaluated whether the SC type could be a risk for AO in a cross-sectional study among Koreans.

Methods

In total, 2,528 subjects aged over 30 years were recruited from 23 medical clinics. We collected waist circumference (WC), weight, height, and some clinical information for AO from the subjects. A Chi-square test and a one-way ANOVA were performed according to SC type (p < .05), while multiple logistic regression was used to produce odds ratios (ORs).

Results

The rates of AO in Tae-eumin (TE), Soeumin (SE), and Soyangin (SY) types were 63.7%, 14.7%, and 32.8% in males and 84.8%, 41.7%, and 52.8% in females, respectively. The TE type was associated with increased AO prevalence compared with the SE and SY types in males (OR 1.79; 95% CI 1.02–3.15, p = 0.044 and OR 1.74; 95% CI 1.18–2.58, p = 0.006, respectively) and females (OR 1.51; 95% CI 1.03–2.23, p = 0.037 and OR 1.88; 95% CI 1.32–2.68, p < 0.001, respectively) after adjusting for age, BMI, hypertension, diabetes mellitus, hypertriglyceridemia, and low HDL cholesterol.

Conclusions

This study suggested that SC, particularly the TE type, might be significantly and independently associated with AO and could be considered a risk factor in predicting AO.
Effective treatment with a tetrandrine/chloroquine combination for chloroquine-resistant falciparum malaria in Aotus monkeys
Authors: Ye Zuguang , Van Dyke Knox , Rossan Richard N
Published: April 2013

Background

In vitro evidence indicates that tetrandrine (TT) can potentiate the action of chloroquine 40-fold against choloquine-resistant Plasmodium falciparum. The key question emanating from that study is “would tetrandine and chloroquine be highly effective in a live Aotus monkey model with chloroquine-resistant parasites”. This study was designed to closely mimic the pharmacological/anti-malarial activity in man.

Methods

The Vietnam Smith/RE strain of P. falciparum, which is chloroquine-resistant was used in this study. Previous experimental procedures were followed. Panamanian owl monkeys (Aotus) were inoculated with 5×106 erythrocytes parasitized with the CQ-resistant strain of P. falciparum. Oral drug treatment was with CQ (20 mg/kg) and/or tetrandrine at 15 mg/Kg, 30 mg/Kg or 60 mg/Kg or 25 mg/Kg depending on experimental conditions.

Results and Discussion

Parasitaemia was cleared rapidly with CQ and TT while CQ treatment alone was ineffective. Recrudescence of malaria occurred after seven days post-infection. However, four animals were treated orally with TT and CQ parasites were cleared. It is likely that monkeys were cured via a combination of both drug and host immune responses. A single Aotus monkey infected with P. falciparum and untreated with drugs, died. No side effects were observed with these drug treatments.

Conclusions

This combination of chloroquine and tetrandrine forms the basis of a new attack on chloroquine-resistant malaria - one based upon inhibition of the basis of chloroquine resistance, the multiple drug resistance pump. Previous studies demonstrated that the parasite MDR pump was found on parasite membranes using 3H azidopine photoaffinity labelling.

Since MDR-based choloroquine resistance is induced by chloroquine, the basis of the action of tetrandrine is the following: 1) tetrandrine inhibits the MDR pump by stimulating MDR ATPase which limits the energy of the pump by depletion of parasite ATP, 2) tetrandrine blocks the genetic factor which controls the induction of the pump. Therefore, it appears that the parasite cannot outsmart these mechanisms and produce a new mode of resistance. Only time will tell if this is correct.
Maternal iron intake at mid-pregnancy is associated with reduced fetal growth: results from Mothers and Children’s Environmental Health (MOCEH) study
Authors: Hwang Ji-Yun , Lee Ji-Yeon , Kim Ki-Nam , Kim Hyesook , Ha Eun-Hee , Park Hyesook , Ha Mina , Kim Yangho , Hong Yun-Chul , Chang Namsoo
Published: April 2013

Background

Iron supplementation is a common recommendation for pregnant women to prevent iron deficiency during pregnancy. There is an increasing concern about excessive iron consumption as a general iron prophylaxis by pregnant women without any due consideration about their dietary iron intake or iron status. Our present study investigated the association between total iron intake from diet and supplements and fetal growth in 337 pregnant women at mid-pregnancy in South Korea.

Methods

Iron intake from diet and supplements was examined by a 24-hour recall method. Subjects were divided into three groups based on tertiles of total iron intake levels. Fetal biometry was assessed by ultrasonography at mid-pregnancy.

Results

About 99% of the non-supplement users had iron intake below the recommended nutrient intake (RNI) for pregnant women (24 mg), whereas 64.9% of supplement users had iron intake above the upper level (UL) (45 mg). In the babies of mothers in the third tertile of iron intake (>17.04 mg), biparietal diameter, abdominal circumference, and femur length were lower by 0.41 cm (P =0.019), 0.41 cm (P = 0.027), and 0.07 cm (P = 0.051), respectively, than the babies of mothers in the second tertile of iron intake (11.49 ~ 17.04 mg).

Conclusion

These results suggest that excessive maternal iron intake at mid-pregnancy is associated with reduced fetal growth. Iron supplementation for pregnant women should be individualized according to their iron status. Appropriate diet education is needed for pregnant women so that they can consume adequate amounts of iron from food and supplements.
Autoinflammatory gene polymorphisms and susceptibility to UK juvenile idiopathic arthritis
Authors: Hinks Anne , Martin Paul , Thompson Susan D , Sudman Marc , Stock Carmel J , Thomson Wendy , Day Thomas G , Packham Jon ,   Childhood arthritis prospective study (CAPS),   BSPAR study group, Ramanan Athimalaipet V , Donn Rachelle P
Published: April 2013

Background

To investigate the autoinflammatory hereditary periodic fever syndrome genes MVK and TNFRSF1A, and the NLRP1 and IL1 genes, for association with juvenile idiopathic arthritis (JIA).

Methods

For MVK, TNFRSF1A and NLRP1 pair-wise tagging SNPs across each gene were selected and for IL1A SNPs from a prior meta-analysis were included. 1054 UK Caucasian JIA patients were genotyped by Sequenom iPlex MassARRAY and allele and genotype frequencies compared with 5380 unrelated healthy UK Caucasian controls.

Results

Four SNPs were significantly associated with UK JIA: rs2071374 within intron 4 of IL1A (ptrend=0.006), rs2228576 3’ of TNFRSF1A (ptrend=0.009) and 2 SNPs, rs11836136 and rs7957619, within MVK (ptrend=0.006, ptrend=0.005 respectively). In all cases the association appeared to be driven by the systemic-onset JIA (SoJIA) subtype. Genotype data for the two MVK SNPs was available in a validation cohort of 814 JIA (oligoarticular and RF negative polyarticular) cases and 3058 controls from the US. Replication was not confirmed, however, further suggesting that this association is specific to SoJIA.

Conclusions

These findings extend the observations of the relevance of studying monogenic loci as candidates for complex diseases. We provide novel evidence of association of MVK and TNFRSF1A with UK JIA, specifically driven by association with SoJIA and further confirm that the IL1A SNP association with SoJIA is subtype specific. Replication is required in independent cohorts.
Efficient CD44-targeted magnetic resonance imaging (MRI) of breast cancer cells using hyaluronic acid (HA)-modified MnFe2O4 nanocrystals
Authors: Lee Taeksu , Lim Eun-Kyung , Lee Jaemin , Kang Byunghoon , Choi Jihye , Park Hyo Seon , Suh Jin-Suck , Huh Yong-Min , Haam Seungjoo
Published: April 2013

Targeted molecular imaging with hyaluronic acid (HA) has been highlighted in the diagnosis and treatment of CD44-overexpressing cancer. CD44, a receptor for HA, is closely related to the growth of cancer including proliferation, metastasis, invasion, and angiogenesis. For the efficient detection of CD44, we fabricated a few kinds of HA-modified MnFe2O4nanocrystals (MNCs) to serve as specific magnetic resonance (MR) contrast agents (HA-MRCAs) and compared physicochemical properties, biocompatibility, and the CD44 targeting efficiency. Hydrophobic MNCs were efficiently phase-transferred using aminated polysorbate 80 (P80) synthesized by introducing spermine molecules on the hydroxyl groups of P80. Subsequently, a few kinds of HA-MRCAs were fabricated, conjugating different ratios of HA on the equal amount of phase-transferred MNCs. The optimized conjugation ratio of HA against magnetic content was identified to exhibit not only effective CD44 finding ability but also high cell viability throughin vitroexperiments. The results of this study demonstrate that the suggested HA-MRCA shows strong potential to be used for accurate tumor diagnosis.
Diameter-sensitive biocompatibility of anodic TiO2 nanotubes treated with supercritical CO2 fluid
Authors: Lan Ming-Ying , Liu Chia-Pei , Huang Her-Hsiung , Chang Jeng-Kuei , Lee Sheng-Wei
Published: April 2013

This work reports on the diameter-sensitive biocompatibility of anodic TiO2 nanotubes with different nanotube diameters grown by a self-ordering process and subsequently treated with supercritical CO2 (ScCO2) fluid. We find that highly hydrophilic as-grown TiO2 nanotubes become hydrophobic after the ScCO2 treatment but can effectively recover their surface wettability under UV light irradiation as a result of photo-oxidation of C-H functional groups formed on the nanotube surface. It is demonstrated that human fibroblast cells show more obvious diameter-specific behavior on the ScCO2-treated TiO2 nanotubes than on the as-grown ones in the range of diameters of 15 to 100 nm. This result can be attributed to the removal of disordered Ti(OH)4 precipitates from the nanotube surface by the ScCO2 fluid, thus resulting in purer nanotube topography and stronger diameter dependence of cell activity. Furthermore, for the smallest diameter of 15 nm, ScCO2-treated TiO2 nanotubes reveal higher biocompatibility than the as-grown sample.
Channel characteristics of MIMO–WLAN communications at 60 GHz for various corridors
Authors: Liao Shu-Han , Chiu Chien-Ching , Chen Chien-Hung , Ho Min-Hui
Published: April 2013

A comparison of 4 × 4 multiple-input multiple-output wireless local area network wireless communication characteristics for six different geometrical shapes is investigated. These six shapes include the straight shape corridor with rectangular cross section, the straight shape corridor with arched cross section, the curved shape corridor with rectangular cross section, the curved shape corridor with arched cross section, the L-shape corridor, and the T-shape corridor. The impulse responses of these corridors are computed by applying shooting and bouncing ray/image (SBR/Image) techniques along with inverse Fourier transform. By using the impulse response of these multipath channels, the mean excess delay, root mean square (RMS) delay spread for these six corridors can be obtained. Numerical results show that the capacity for the rectangular cross section corridors is smaller than those for the arched cross section corridors regardless of the shapes. And the RMS delay spreads for the T-and the L-shape corridors are greater than the other corridors.
Reduced contribution of thermally labile sugar lesions to DNA double strand break formation after exposure to heavy ions
Authors: Singh Satyendra K , Bencsik-Theilen Alena , Mladenov Emil , Jakob Burkhard , Taucher-Scholz Gisela , Iliakis George
Published: April 2013

In cells exposed to low linear energy transfer (LET) ionizing-radiation (IR),double-strand-breaks (DSBs) form within clustered-damage-sites (CDSs) fromlesions disrupting the DNA sugar-phosphate backbone. It is commonly assumed thatall DSBs form promptly and are immediately detected by the cellularDNA-damage-response (DDR) apparatus. However, there is evidence that the pool ofDSBs detected by physical methods, such as pulsed-field gel electrophoresis(PFGE), comprises not only promptly forming DSBs (prDSBs) but also DSBsdeveloping during lysis at high temperatures from thermally-labile sugar-lesions(TLSLs). We recently demonstrated that conversion of TLSLs to DNA breaks andultimately to DSBs also occurs in cells during the first hour ofpost-irradiation incubation at physiological temperatures. Thus, TLSL-dependentDSBs (tlDSBs) are not an avoidable technique-related artifact, but a reality thecell always faces. The biological consequences of tlDSBs and the dependence oftheir formation on LET require in-depth investigation. Heavy-ions (HI) are apromising high-LET radiation modality used in cancer treatment. HI are alsoencountered in space and generate serious radiation protection problems toprolonged space missions. Here, we study, therefore, the effect of HI on theyields of tlDSBs and prDSBs. We report a reduction in the yield of tlDBSsstronger than that earlier reported for neutrons, and with pronounced cell linedependence. We conclude that with increasing LET the complexity of CDSsincreases resulting in a commensurate increase in the yield prDSBs and adecrease in tlDSBs. The consequences of these effects to the relative biologicaleffectiveness are discussed.
Structurally differentiated cis-elements that interact with PU.1 are functionally distinguishable in acute promyelocytic leukemia
Authors: Qian Maoxiang , Jin Wen , Zhu Xuehua , Jia Xiaohong , Yang Xianwen , Du Yanzhi , Wang Kankan , Zhang Ji
Published: April 2013

Background

Transcription factor PU.1, a member of the ETS family, is a master regulator of myeloid differentiation whose functional disruption is often associated with acute myeloid leukemia (AML). Although much has been learned about PU.1 over the past decades, relatively little is known aboutcis-elements that interact with this factor under physiological or pathological conditions, especially in the whole-genome scale. We aimed to define the cistrome of PU.1 in acute promyelocytic leukemia (APL) cells and characterize thecis-elements bound by PU.1.

Methods

Chromatin immunoprecipitation with specific antibody coupled with deep sequencing (ChIP-seq) was used to investigate thein vivoPU.1 binding sites at the whole-genome scale in APL-derived NB4 cells. The ChIP-quantitative (q)-PCR and luciferase reporter assays were used to validate the binding events andtrans-activity, respectively. Various computational analyses, including motif mining, evolutionary conservation analysis and functional enrichment analysis, were performed to characterize thecis-elements that interacted with PU.1.

Results

A total of 26,907 significantly enriched binding regions of PU.1 were identified under the false discovery rate 0.1% in NB4 cells. PU.1 bound to various types of genomic regions and acted as a promoter-enhancer dual binding transcription factor. Based on the sequence length and composition, two types of representative motifs were identified in PU.1 binding sites: a long and a short motif. The long motif, characterized by high sequence specificity and binding affinity, predominantly resided in the promoter-distal regions. In contrast, the short one, with strong evolutionary constraint, represented the primary PU.1cis-elements in the promoter-proximal regions. Interestingly, the short one showed more preference to be correlated with the binding of other factors, especially PML/RARα. Moreover, genes targeted by both PU.1 and PML/RARα were significantly involved in categories associated with oncogenesis, hematopoiesis and the pathogenesis of acute myeloid leukemia.

Conclusions

Our results demonstrate that structurally differentiatedcis-elements that interact with PU.1 are functionally distinguishable in APL, suggesting that the sequence diversity ofcis-elements might be a critical mechanism by which cells interpret the genome, and contribute to distinct physiological and/or pathological function.
Krüppel-like factor 6 (KLF6) promotes cell proliferation in skeletal myoblasts in response to TGFβ/Smad3 signaling
Authors: Dionyssiou Mathew G , Salma Jahan , Bevzyuk Mariya , Wales Stephanie , Zakharyan Lusine , McDermott John C
Published: April 2013

Background

Krüppel-like factor 6 (KLF6) has been recently identified as a MEF2D target gene involved in neuronal cell survival. In addition, KLF6 and TGFβ have been shown to regulate each other’s expression in non-myogenic cell types. Since MEF2D and TGFβ also fulfill crucial roles in skeletal myogenesis, we wanted to identify whether KLF6 functions in a myogenic context.

Methods

KLF6 protein expression levels and promoter activity were analyzed using standard cellular and molecular techniques in cell culture.

Results

We found that KLF6 and MEF2D are co-localized in the nuclei of mononucleated but not multinucleated myogenic cells and, that the MEF2 cis element is a key component of the KLF6 promoter region. In addition, TGFβ potently enhanced KLF6 protein levels and this effect was repressed by pharmacological inhibition of Smad3. Interestingly, pharmacological inhibition of MEK/ERK (1/2) signaling resulted in re-activation of the differentiation program in myoblasts treated with TGFβ, which is ordinarily repressed by TGFβ treatment. Conversely, MEK/ERK (1/2) inhibition had no effect on TGFβ-induced KLF6 expression whereas Smad3 inhibition negated this effect, together supporting the existence of two separable arms of TGFβ signaling in myogenic cells. Loss of function analysis using siRNA-mediated KLF6 depletion resulted in enhanced myogenic differentiation whereas TGFβ stimulation of myoblast proliferation was reduced in KLF6 depleted cells.

Conclusions

Collectively these data implicate KLF6 in myoblast proliferation and survival in response to TGFβ with consequences for our understanding of muscle development and a variety of muscle pathologies.
Timing of renal replacement therapy initiation by AKIN classification system
Authors: Leite Tacyano T , Macedo Etienne , Pereira Samuel M , Bandeira Sandro RC , Pontes Pedro HS , Garcia André S , Militão Fernanda R , Sobrinho Irineu MM , Assunção Livia M , Libório Alexandre B
Published: April 2013

Introduction

Previous studies using Acute Kidney Injury Network (AKIN)/RIFLE criteria to classify early initiation of renal replacement therapy (RRT) have defined it as the therapy started in less severe AKIN/RIFLE stages. Generally, these studies failed in demonstrating measurable benefits.

Methods

We compared RRT initiation in critically ill patients and defined early or late RRT in reference to timing after stage 3 AKIN was met: patients beginning RRT within 24 hours after acute kidney injury (AKI) stage 3 were considered early starters. AKIN criteria were evaluated by both urine output (UO) and serum creatinine (sCr) and patients with acute-on-chronic kidney disease were excluded. A propensity score methodology was used to control variables.

Results

A total of 358 critically ill patients were submitted to RRT. Only 150 patients with pure AKI at stage 3 were analyzed. Mortality was lower in the early RRT group (51.5 vs. 77.9%, P = 0.001). After achieving balance between the groups using a propensity score, there was a significant 30.5 (95% confidence interval [CI] 14.4 to 45.2%, P = 0.002) relative decrease of mortality in the early RRT group. Moreover, patients on the early RRT group had lower duration of mechanical ventilation, time on RRT and a trend to lower intensive care unit (ICU) length of stay.

Conclusions

For the first time, AKIN was used with UO criterion to evaluate early and late RRT. Using a time-based approach could be a better parameter to access the association between RRT initiation and outcomes in patients with AKI.
The western painted turtle genome, a model for the evolution of extreme physiological adaptations in a slowly evolving lineage
Authors: Bradley Shaffer H , Minx Patrick , Warren Daniel E , Shedlock Andrew M , Thomson Robert C , Valenzuela Nicole , Abramyan John , Amemiya Chris T , Badenhorst Daleen , Biggar Kyle K , Borchert Glen M , Botka Christopher W , Bowden Rachel M , Braun Edward L , Bronikowski Anne M , Bruneau Benoit G , Buck Leslie T , Capel Blanche , Castoe Todd A , Czerwinski Mike , Delehaunty Kim D , Edwards Scott V , Fronick Catrina C , Fujita Matthew K , Fulton Lucinda , Graves Tina A , Green Richard E , Haerty Wilfried , Hariharan Ramkumar , Hernandez Omar , Hillier LaDeana W , Holloway Alisha K , Janes Daniel , Janzen Fredric J , Kandoth Cyriac , Kong Lesheng , de Koning AP Jason , Li Yang , Literman Robert , McGaugh Suzanne E , Mork Lindsey , O'Laughlin Michelle , Paitz Ryan T , Pollock David D , Ponting Chris P , Radhakrishnan Srihari , Raney Brian J , Richman Joy M , St John John , Schwartz Tonia , Sethuraman Arun , Spinks Phillip Q , Storey Kenneth B , Thane Nay , Vinar Tomas , Zimmerman Laura M , Warren Wesley C , Mardis Elaine R , Wilson Richard K
Published: April 2013

Background

We describe the genome of the western painted turtle, Chrysemys picta bellii, one of the most widespread, abundant, and well-studied turtles. We place the genome into a comparative evolutionary context, and focus on genomic features associated with tooth loss, immune function, longevity, sex differentiation and determination, and the species' physiological capacities to withstand extreme anoxia and tissue freezing.

Results

Our phylogenetic analyses confirm that turtles are the sister group to living archosaurs, and demonstrate an extraordinarily slow rate of sequence evolution in the painted turtle. The ability of the painted turtle to withstand complete anoxia and partial freezing appears to be associated with common vertebrate gene networks, and we identify candidate genes for future functional analyses. Tooth loss shares a common pattern of pseudogenization and degradation of tooth-specific genes with birds, although the rate of accumulation of mutations is much slower in the painted turtle. Genes associated with sex differentiation generally reflect phylogeny rather than convergence in sex determination functionality. Among gene families that demonstrate exceptional expansions or show signatures of strong natural selection, immune function and musculoskeletal patterning genes are consistently over-represented.

Conclusions

Our comparative genomic analyses indicate that common vertebrate regulatory networks, some of which have analogs in human diseases, are often involved in the western painted turtle's extraordinary physiological capacities. As these regulatory pathways are analyzed at the functional level, the painted turtle may offer important insights into the management of a number of human health disorders.
Oral administration of carbonic anhydrase I ameliorates murine experimental colitis induced by Foxp3−CD4+CD25− T cells
Authors: Mori Kenichirou , Yamanishi Hirofumi , Ikeda Yoshiou , Kumagi Teru , Hiasa Yoichi , Matsuura Bunzo , Abe Masanori , Onji Morikazu
Published: April 2013

Oral tolerization with carbonic anhydrase I induces antigen-specific protection from murine experimental colitis, by inducing CD103+ dendritic cells and generating Foxp3+CD4+CD25+ regulatory T cells.

IBDs are thought to involve uncontrolled innate and adaptive immunity against intestinal self-antigens and bacterial antigens. Mouse CA I is a major cecal bacterial antigen in fecal extracts and is implicated in the pathogenesis of IBD. We show here that oral tolerization to CA I induced antigen-specific protection from intestinal inflammation in a murine model. Oral administration of CA I but not irrelevant antigen (KLH) ameliorated CD4+CD25− T cell transfer murine colitis and DSS-induced murine colitis. Next, we investigated the mechanisms involved in the therapeutic effects of oral administration, such as induction of ALDH1a2, transcription factors, cytokines, CD103+CD11c+ DCs, and generation of Tregs. Oral administration of CA I induced ALDH1a2 mRNA expression in the MLN and colon. When compared with PBS-treated mice, CA I-treated mice had higher Foxp3+CD4+CD25+ Treg and CD103+CD11c+ DC numbers in the MLN and colon; had higher TGF-β production in the MLN and colon; had lower RORγt mRNA expression in the MLN and colon; and had lower IL-17 mRNA expression and production in the MLN. These results demonstrate that oral administration of CA I induced antigen-specific immune tolerance by generating Foxp3+CD4+CD25+ Tregs and inhibiting Th17 cells in a murine colitis model, thus suggesting that oral tolerization with CA I is an effective therapeutic strategy for IBD regulation.
The balanced care model: the case for both hospital- and community-based mental healthcare
Authors: Thornicroft Graham , Tansella Michele
Published: April 2013

The balanced care model proposes that a comprehensive mental health system needs to include both community-and hospital-based care. The model is based on a structured review of scientific evidence, and is also informed by the experience of experts active in mental health system change in many countries worldwide.
Commissioning services for people with dementia: how to get it right
Authors: Iliffe Steve
Published: April 2013

The current emphasis on improving the quality of dementia services is welcome, but it treats dementia as if it were separable from complex comorbidities, disability and frailty. As a consequence, dementia can overshadow other problems, from heart failure to multisystem failure at the end of life, which may be poorly managed. Three ways in which old age psychiatrists can reconnect dementia with the diseases and disorders of later life are described in this editorial. The first is to improve skills in general practice so that general practitioners (GPs) can take on the bulk of the clinical work of both diagnosis and management of dementia and its comorbidities, while specialists retain complex decision-making and management tasks. The second is for old age psychiatrists to function as consultants to social enterprises run by GPs for the purpose of managing almost all patients with dementia in general practice. The third is for community geriatricians and old age psychiatrists to work together in integrated organisations that take full clinical responsibility for older people with dementia.
Use of specialist services for obsessive–compulsive and body dysmorphic disorders across England
Authors: Drummond Lynne M. , Fineberg Naomi A. , Heyman Isobel , Veale David , Jessop Edmond
Published: April 2013

Aims and method

In April 2007, the National Specialist Commissioning Team of the Department of Health commissioned a group of services to provide treatment to patients with the most severe and profound obsessive-compulsive disorder (OCD) and body dysmorphic disorder (BDD). We decided to examine the usage of these services across England 4–5 years after the start of the new funding arrangements. This survey used data about patients treated in the financial year 2011–2012.

Results

Despite the services offering intensive home-based as well as residential and in-patient services, there was a greater proportion of referrals from London, the South East of England and counties closer to London.

Clinical implications

It is important that all patients, regardless of where they live, have access to highly specialist services for OCD and BDD. We discuss potential ways of improving this access but we hope this paper will act as a discussion forum whereby we can receive feedback from others.
Sequential Phase I and II Trials of Stereotactic Body Radiotherapy for Locally Advanced Hepatocellular Carcinoma
Authors: Bujold Alexis , Massey Christine A. , Kim John J. , Brierley James , Cho Charles , Wong Rebecca K.S. , Dinniwell Rob E. , Kassam Zahra , Ringash Jolie , Cummings Bernard , Sykes Jenna , Sherman Morris , Knox Jennifer J. , Dawson Laura A.
Published: April 2013

Purpose

To describe outcomes of prospective trials of stereotactic body radiotherapy (SBRT) for hepatocellular carcinoma (HCC).

Patients and Methods

Two trials of SBRT for patients with active HCC unsuitable for standard locoregional therapies were conducted from 2004 to 2010. All patients had Child-Turcotte-Pugh class A disease, with at least 700 mL of non-HCC liver. The SBRT dose range was 24 to 54 Gy in six fractions. Primary end points were toxicity and local control at 1 year (LC1y), defined as no progressive disease (PD) of irradiated HCC by RECIST (Response Evaluation Criteria in Solid Tumors).

Results

A total of 102 patients were evaluable (Trial 1, 2004 to 2007: n = 50; Trial 2, 2007 to 2010: n = 52). Underlying liver disease was hepatitis B in 38% of patients, hepatitis C in 38%, alcohol related in 25%, other in 14%, and none in 7%. Fifty-two percent received prior therapies (no prior sorafenib). TNM stage was III in 66%, and 61% had multiple lesions. Median gross tumor volume was 117.0 mL (range, 1.3 to 1,913.4 mL). Tumor vascular thrombosis (TVT) was present in 55%, and extrahepatic disease was present in 12%. LC1y was 87% (95% CI, 78% to 93%). SBRT dose (hazard ratio [HR] = 0.96; P = .02) and being in Trial 2 (HR = 0.38; P = .03) were associated with LC1y on univariate analysis. Toxicity ≥ grade 3 was seen in 30% of patients. In seven patients (two with TVT PD), death was possibly related to treatment (1.1 to 7.7 months after SBRT). Median overall survival was 17.0 months (95% CI, 10.4 to 21.3 months), for which only TVT (HR = 2.47; P = .01) and being in Trial 2 (HR = 0.49; P = .01) were significant on multivariate analysis.

Conclusion

These results provide strong rationale for studying SBRT for HCC in a randomized trial.
90Yttrium-Ibritumomab Tiuxetan Consolidation of First Remission in Advanced-Stage Follicular Non-Hodgkin Lymphoma: Updated Results After a Median Follow-Up of 7.3 Years From the International, Randomized, Phase III First-Line Indolent Trial
Authors: Morschhauser Franck , Radford John , Van Hoof Achiel , Botto Barbara , Rohatiner Ama Z.S. , Salles Gilles , Soubeyran Pierre , Tilly Herve , Bischof-Delaloye Angelika , van Putten Wim L.J. , Kylstra Jelle W. , Hagenbeek Anton
Published: April 2013

Purpose

Updated results are presented after a median follow-up of 7.3 years from the phase III First-Line Indolent Trial of yttrium-90 (90Y) –ibritumomab tiuxetan in advanced-stage follicular lymphoma (FL) in first remission.

Patients and Methods

Patients with CD20+ stage III or IV FL with complete response (CR), unconfirmed CR (CRu), or partial response (PR) after first-line induction treatment were randomly assigned to 90Y-ibritumomab consolidation therapy (rituximab 250 mg/m2 days −7 and 0, then 90Y-ibritumomab 14.8 MBq/kg day 0; maximum 1,184 MBq) or no further treatment (control). Primary end point was progression-free survival (PFS) from date of random assignment.

Results

For 409 patients available for analysis (90Y-ibritumomab, n = 207; control, n = 202), estimated 8-year overall PFS was 41% with 90Y-ibritumomab versus 22% for control (hazard ratio [HR], 0.47; P < .001). For patients in CR/CRu after induction, 8-year PFS with 90Y-ibritumomab was 48% versus 32% for control (HR, 0.61; P = .008), and for PR patients, it was 33% versus 10% (HR, 0.38; P < .001). For 90Y-ibritumomab consolidation, median PFS was 4.1 years (v 1.1 years for control; P < .001). Median time to next treatment (TTNT) was 8.1 years for 90Y-ibritumomab versus 3.0 years for control (P < .001) with approximately 80% response rates to second-line therapy in either arm, including autologous stem-cell transplantation. No unexpected toxicities emerged during long-term follow-up. Estimated between-group 8-year overall survival rates were similar. Annualized incidence rate of myelodysplastic syndrome/acute myeloblastic leukemia was 0.50% versus 0.07% in 90Y-ibritumomab and control groups, respectively (P = .042).

Conclusion

90Y-ibritumomab consolidation after achieving PR or CR/CRu to induction confers 3-year benefit in median PFS with durable 19% PFS advantage at 8 years and improves TTNT by 5.1 years for patients with advanced FL.
17β-Estradiol Activates Glucose Uptake via GLUT4 Translocation and PI3K/Akt Signaling Pathway in MCF-7 Cells
Authors: Garrido Pablo , Morán Javier , Alonso Ana , González Segundo , González Celestino
Published: April 2013

The relationship between estrogen and some types of breast cancer has been clearly established. However, although several studies have demonstrated the relationship between estrogen and glucose uptake via phosphatidylinositol 3-kinase (PI3K)/Akt in other tissues, not too much is known about the possible cross talk between them for development and maintenance of breast cancer. This study was designed to test the rapid effects of 17β-estradiol (E2) or its membrane-impermeable form conjugated with BSA (E2BSA) on glucose uptake in a positive estrogen receptor (ER) breast cancer cell line, through the possible relationship between key components of the PI3K/Akt signaling pathway and acute steroid treatment. MCF-7 human breast cancer cells were cultured in standard conditions. Then 10 nM E2 or E2BSA conjugated were administered before obtaining the cell lysates. To study the glucose uptake, the glucose fluorescent analog 2-[N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino]-2-deoxy-d-glucose was used. We report an ER-dependent activation of some of the key steps of the PI3K/Akt signaling pathway cascade that leads cells to improve some mechanisms that finally increase glucose uptake capacity. Our data suggest that both E2 and E2BSA enhance the entrance of the fluorescent glucose analog 2-[N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino]-2-deoxy-d-glucose, and also activates PI3K/Akt signaling pathway, leading to translocation of glucose transporter 4 to the plasma membrane in an ERα-dependent manner. E2 enhances ER-dependent rapid signaling triggered, partially in the plasma membrane, allowing ERα-positive MCF-7 breast cancer cells to increase glucose uptake, which could be essential to meet the energy demands of the high rate of proliferation.
Importance of Cysteine Residues in the Thyroid Hormone Transporter MCT8
Authors: Lima de Souza Elaine C. , Groeneweg Stefan , Visser W. Edward , Peeters Robin P. , Visser Theo J.
Published: April 2013

The thyroid hormone (TH) transporter monocarboxylate transporter 8 (MCT8) is crucial for brain development as demonstrated by the severe psychomotor retardation in patients with MCT8 mutations. MCT8 contains 10 residues of the reactive amino acid cysteine (Cys) whose functional roles were studied using the Cys-specific reagent p-chloromercurybenzenesulfonate (pCMBS) and by site-directed mutagenesis. Pretreatment of JEG3 cells with pCMBS resulted in a dose- and time-dependent decrease of subsequent T3 uptake. Pretreatment with dithiothreitol did not affect TH transport or its inhibition by pCMBS. However, pCMBS inhibition of MCT8 was reversed by dithiothreitol. Inhibition of MCT8 by pCMBS was prevented in the presence of T3. The single and double mutation of C481A and C497A did not affect T3 transport, but the single mutants were less sensitive and the double mutant was completely insensitive to pCMBS. Similar effects on MCT8 were obtained using HgCl2 instead of pCMBS. In conclusion, we have identified Cys481 and Cys497 in MCT8 as the residues modified by pCMBS or HgCl2. These residues are probably located at or near the substrate-recognition site in MCT8. It remains to be investigated whether MCT8 function is regulated by modification of these Cys residues under pathophysiological conditions.