bluuebunny/crossref_metadata_2025_split huggingface dataset:
Genetic and functional association of FAM5C with myocardial infarction
Authors: Connelly Jessica J , Shah Svati H , Doss Jennifer F , Gadson Shera , Nelson Sarah , Crosslin David R , Hale A Brent , Lou Xuemei , Wang Ty , Haynes Carol , Seo David , Crossman David C , Mooser Vincent , Granger Christopher B , Jones Christopher JH , Kraus William E , Hauser Elizabeth R , Gregory Simon G 
Published: April 2008

AbstractBackgroundWe previously identified a 40 Mb region of linkage on chromosome 1q in our early onset coronary artery disease (CAD) genome-wide linkage scan (GENECARD) with modest evidence for linkage (n = 420, LOD 0.95). When the data are stratified by acute coronary syndrome (ACS), this modest maximum in the overall group became a well-defined LOD peak (maximum LOD of 2.17, D1S1589/D1S518). This peak overlaps a recently identified inflammatory biomarker (MCP-1) linkage region from the Framingham Heart Study (maximum LOD of 4.27, D1S1589) and a region of linkage to metabolic syndrome from the IRAS study (maximum LOD of 2.59, D1S1589/D1S518). The overlap of genetic screens in independent data sets provides evidence for the existence of a gene or genes for CAD in this region.MethodsA peak-wide association screen (457 SNPs) was conducted of a region 1 LOD score down from the peak marker (168–198 Mb) in a linkage peak for acute coronary syndrome (ACS) on chromosome 1, within a family-based early onset coronary artery disease (CAD) sample (GENECARD).ResultsPolymorphisms were identified within the 'family with sequence similarity 5, member C' gene (FAM5C) that show genetic linkage to and are associated with myocardial infarction (MI) in GENECARD. The association was confirmed in an independent CAD case-control sample (CATHGEN) and strong association with MI was identified with single nucleotide polymorphisms (SNPs) in the 3' end ofFAM5C.FAM5Cgenotypes were also correlated with expression of the gene in human aorta. Expression levels ofFAM5Cdecreased with increasing passage of proliferating aortic smooth muscle cells (SMC) suggesting a role for this molecule in smooth muscle cell proliferation and senescence.ConclusionThese data implicateFAM5Calleles in the risk of myocardial infarction and suggest further functional studies ofFAM5Care required to identify the gene's contribution to atherosclerosis.
A randomised clinical trial of subgrouping and targeted treatment for low back pain compared with best current care. The STarT Back Trial Study Protocol
Authors: Hay Elaine M , Dunn Kate M , Hill Jonathan C , Lewis Martyn , Mason Elizabeth E , Konstantinou Kika , Sowden Gail , Somerville Simon , Vohora Kanchan , Whitehurst David , Main Chris J 
Published: April 2008

Abstract

Background
Back pain is a major health problem and many sufferers develop persistent symptoms. Detecting relevant subgroups of patients with non-specific low back pain has been highlighted as a priority area for research, as this could enable better secondary prevention through the targeting of prognostic indicators for persistent, disabling symptoms. We plan to conduct a randomised controlled trial to establish whether subgrouping using a novel tool, combined with targeted treatment, is better than best current care at reducing long-term disability from low back pain.

Methods/Design
We will recruit 800 participants aged 18 years and over with non-specific low back pain from 8–10 GP practices within two Primary Care Trusts in Staffordshire, England. Our primary outcome measures are low back pain disability and catastrophising. Secondary outcomes include back pain intensity, global change, leg pain, fear avoidance, anxiety, depression, illness perceptions, patient satisfaction, overall health status and cost-effectiveness. Data will be collected before randomisation, and 4 and 12 months later. Participants are randomised to receive either newly developed interventions, delivered by trained physiotherapists and targeted according to subgroups defined by tool scores, or best current care.

Discussion
This paper presents detail on the rationale, design, methods and operational aspects of the trial.

Trial registration
Current Controlled Trials ISRCTN37113406.
Effect of a proprietary Magnolia and Phellodendronextract on stress levels in healthy women: a pilot, double-blind, placebo-controlled clinical trial
Authors: Kalman Douglas S , Feldman Samantha , Feldman Robert , Schwartz Howard I , Krieger Diane R , Garrison Robert 
Published: April 2008

AbstractBackgroundRecent research has established correlations between stress, anxiety, insomnia and excess body weight and these correlations have significant implications for health. This study measured the effects of a proprietary blend of extracts ofMagnolia officinalisandPhellodendron amurense (Relora®) on anxiety, stress and sleep in healthy premenopausal women.MethodsThis randomized, parallel, placebo controlled clinical studywas conducted with healthy, overweight (BMI 25 to 34.9), premenopausal female adults, between the ages of 20 and 50 years, who typically eat more in response to stressful situations and scores above the national mean for women on self-reporting anxiety. The intervention wasRelora (250 mg capsules) or identical placebo 3 times daily for 6 weeks. Anxiety as measured by the Spielberger STATE-TRAIT questionnaires, salivary amylase and cortisol levels, Likert Scales/Visual Analog Scores for sleep quality and latency, appetite, and clinical markers of safety. The study was conducted by Miami Research Associates, a clinical research organization in Miami, FL.ResultsThe intent-to-treat population consisted of 40 subjects with 26 participants completing the study. There were no significant adverse events. Relora was effective, in comparison to placebo, in reducing temporary, transitory anxiety as measured by the Spielberger STATE anxiety questionnaire. It was not effective in reducing long-standing feelings of anxiety or depression as measured using the Spielberger TRAIT questionnaire. Other assessments conducted in this study including salivary cortisol and amylase levels, appetite, body morphology and sleep quality/latency were not significantly changed by Relora in comparison to placebo.ConclusionThis pilot study indicates that Relora may offer some relief for premenopausal women experiencing mild transitory anxiety. There were no safety concerns or significant adverse events observed in this study.
Mycobacterium avium subspecies paratuberculosis is not associated with Type-2 Diabetes Mellitus
Authors: Rosu Valentina , Ahmed Niyaz , Paccagnini Daniela , Pacifico Adolfo , Zanetti Stefania , Sechi Leonardo A 
Published: April 2008

Abstract

Background
The role of pathogenic mycobacteria in diabetes has been a focus of speculation since a decade without any meaningful insights into the mechanism of diabetes causation vis a vis mycobacterial factors. Two of our studies based on PCR identification of mycobacterial DNA and detection of antibodies specific to the recombinant antigens and whole cell lysates of the Mycobacterium avium subsp. paratuberculosis (MAP) shown a clear association of MAP with the presence of type 1 diabetes mellitus (T1DM).

Methods
In this study, we sought to investigate if or not type 2 diabetes (T2DM) patients harbour humoral responses to MAP. Using three different MAP antigen preparations, humoral antibody profiles were estimated for 57 T2DM patients and 57 healthy controls. Statistical analysis was performed with the Chi-square test with Yates' corrections.

Results
We observed insignificant levels of humoral antibodies against recombinant heparin binding haemagglutinin (HbHA), glycosyl transferase (Gsd) and MAP whole cell lysate in the blood of subjects with T2DM as compared to healthy controls.

Conclusion
We found no obvious association of MAP with the incidence of T2DM in Sardinian patients.
DNA-dependent protein kinase catalytic subunit modulates the stability of c-Myc oncoprotein
Authors: An Jing , Yang Dong-Yan , Xu Qin-Zhi , Zhang Shi-Meng , Huo Yan-Ying , Shang Zeng-Fu , Wang Yu , Wu De-Chang , Zhou Ping-Kun 
Published: April 2008

Abstract

Background
C-Myc is a short-lived oncoprotein that is destroyed by ubiquitin-mediated proteolysis. Dysregulated accumulation of c-Myc commonly occurs in human cancers. Some of those cases with the dysregulated c-Myc protein accumulation are attributed to gene amplification or increased mRNA expression. However, the abnormal accumulation of c-Myc protein is also a common finding in human cancers with normal copy number and transcription level of c-Myc gene. It seems that the mechanistic dysregulation in the control of c-Myc protein stabilization is another important hallmark associated with c-Myc accumulation in cancer cells. Here we report a novel mechanistic pathway through which DNA-dependent protein kinase catalytic subunit (DNA-PKcs) modulates the stability of c-Myc protein.

Results
Firstly, siRNA-mediated silencing of DNA-PKcs strikingly downregulated c-Myc protein levels in HeLa and HepG2 cells, and simultaneously decreased cell proliferation. The c-Myc protein level in DNA-PKcs deficient human glioma M059J cells was also found much lower than that in DNA-PKcs efficient M059K cells. ATM deficiency does not affect c-Myc expression level. Silencing of DNA-PKcs in HeLa cells resulted in a decreased stability of c-Myc protein, which was associated the increasing of c-Myc phosphorylation on Thr58/Ser62 and ubiquitination level. Phosphorylation of Akt on Ser473, a substrate of DNA-PKcs was found decreased in DNA-PKcs deficient cells. As the consequence, the phosphorylation of GSK3 β on Ser9, a negatively regulated target of Akt, was also decreased, and which led to activation of GSK 3β and in turn phosphorylation of c-Myc on Thr58. Moreover, inhibition of GSK3 activity by LiCl or specific siRNA molecules rescued the downregulation of c-Myc mediated by silencing DNA-PKcs. Consistent with this depressed DNA-PKcs cell model, overexpressing DNA-PKcs in normal human liver L02 cells, by sub-chronically exposing to very low dose of carcinogen 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), increased c-Myc protein level, the phosphorylation of Akt and GSK3 β, as well as cell proliferation. siRNA-mediated silencing of DNA-PKcs in this cell model reversed above alterations to the original levels of L02 cells.

Conclusion
A suitable DNA-PKcs level in cells is necessary for maintaining genomic stability, while abnormal overexpression of DNA-PKcs may contribute to cell proliferation and even oncogenic transformation by stabilizing the c-Myc oncoprotein via at least the Akt/GSK3 pathway. Our results suggest DNA-PKcs a novel biological role beyond its DNA repair function.
Synergistic effects of high fat feeding and apolipoprotein E deletion on enterocytic amyloid-beta abundance
Authors: Galloway Susan , Pallebage-Gamarallage Menuka MS , Takechi Ryusuke , Jian Le , Johnsen Russell D , Dhaliwal Satvinder S , Mamo John CL 
Published: April 2008

Abstract

Background
Amyloid-β (Aβ), a key protein found in amyloid plaques of subjects with Alzheimer's disease is expressed in the absorptive epithelial cells of the small intestine. Ingestion of saturated fat significantly enhances enterocytic Aβ abundance whereas fasting abolishes expression. Apolipoprotein (apo) E has been shown to directly modulate Aβ biogenesis in liver and neuronal cells but it's effect in enterocytes is not known. In addition, apo E modulates villi length, which may indirectly modulate Aβ as a consequence of differences in lipid absorption. This study compared Aβ abundance and villi length in wild-type (WT) and apo E knockout (KO) mice maintained on either a low-fat or high-fat diet. Wild-type C57BL/6J and apo E KO mice were randomised for six-months to a diet containing either 4% (w/w) unsaturated fats, or chow comprising 16% saturated fats and 1% cholesterol. Quantitative immunohistochemistry was used to assess Aβ abundance in small intestinal enterocytes. Apo E KO mice given the low-fat diet had similar enterocytic Aβ abundance compared to WT controls.

Results
The saturated fat diet substantially increased enterocytic Aβ in WT and in apo E KO mice, however the effect was greater in the latter. Villi height was significantly greater in apo E KO mice than for WT controls when given the low-fat diet. However, WT mice had comparable villi length to apo E KO when fed the saturated fat and cholesterol enriched diet. There was no effect of the high-fat diet on villi length in apo E KO mice.

Conclusion
The findings of this study are consistent with the notion that lipid substrate availability modulates enterocytic Aβ. Apo E may influence enterocytic lipid availability by modulating absorptive capacity.
Characteristic expression of HTLV-1 basic zipper factor (HBZ) transcripts in HTLV-1 provirus-positive cells
Authors: Usui Tetsuya , Yanagihara Katsunori , Tsukasaki Kunihiro , Murata Ken , Hasegawa Hiroo , Yamada Yasuaki , Kamihira Shimeru 
Published: April 2008

Abstract

Background
HTLV-1 causes adult T-cell leukemia (ATL). Although there have been many studies on the oncogenesis of the viral protein Tax, the precise oncogenic mechanism remains to be elucidated. Recently, a new viral factor, HTLV-1 basic Zip factor (HBZ), encoded from the minus strand mRNA was discovered and the current models of Tax-centered ATL cell pathogenesis are in conflict with this discovery. HBZs consisting of non-spliced and spliced isoforms (HBZ-SI) are thought to be implicated in viral replication and T-cell proliferation but there is little evidence on the HBZ expression profile on a large scale.

Results
To investigate the role of HBZ-SI in HTLV-1 provirus-positive cells, the HBZ-SI and Tax mRNA loads in samples with a mixture of infected and non-infected cells were measured and then adjusted by dividing by the HTLV-I proviral load. We show here that the HBZ-SI mRNA level is 4-fold higher than non-spliced HBZ and is expressed by almost all cells harboring HTLV-1 provirus with variable intensity. The proviral-adjusted HBZ-SI and Tax quantification revealed a characteristic imbalanced expression feature of high HBZ and low Tax expression levels in primary ATL cells or high HBZ and very high Tax levels in HTLV-1-related cell lines (cell lines) compared with a standard expression profile of low HBZ and low Tax in infected cells. Interestingly, according to the mutual Tax and HBZ expression status, HTLV-1-related cell lines were subcategorized into two groups, an ATL cell type with high HBZ and low Tax levels and another type with high Tax and either high or low HBZ, which was closely related to its cell origin.

Conclusion
This is the first comprehensive study to evaluate the mutual expression profile of HBZ and Tax in provirus-positive cells, revealing that there are quantitative and relative characteristic features among infected cells, primary ATL cells, and cell lines.
Investigation of the hydrodynamic properties of a new MRI-resistant programmable hydrocephalus shunt
Authors: Allin David M , Czosnyka Marek , Richards Hugh K , Pickard John D , Czosnyka Zofia H 
Published: April 2008

Abstract

Background
The Polaris valve is a newly released hydrocephalus shunt that is designed to drain cerebrospinal fluid (CSF) from the brain ventricles or lumbar CSF space. The aim of this study was to bench test the properties of the Polaris shunt, independently of the manufacturer.

Methods
The Polaris Valve is a ball-on-spring valve, which can be adjusted magnetically in vivo. A special mechanism is incorporated to prevent accidental re-adjustment by an external magnetic field. The performance and hydrodynamic properties of the valve were evaluated in the UK Shunt Evaluation Laboratory, Cambridge, UK.

Results
The three shunts tested showed good mechanical durability over the 3-month period of testing, and a stable hydrodynamic performance over 45 days. The pressure-flow performance curves, operating, opening and closing pressures were stable. The drainage rate of the shunt increased when a negative outlet pressure (siphoning) was applied. The hydrodynamic parameters fell within the limits specified by the manufacturer and changed according to the five programmed performance levels. Hydrodynamic resistance was dependant on operating pressure, changing from low values of 1.6 mmHg/ml/min at the lowest level to 11.2 mmHg/ml/min at the highest performance level. External programming proved to be easy and reliable. Even very strong magnetic fields (3 Tesla) were not able to change the programming of the valve. However, distortion of magnetic resonance images was present.

Conclusion
The Polaris Valve is a reliable, adjustable valve. Unlike other adjustable valves (except the Miethke ProGAV valve), the Polaris cannot be accidentally re-adjusted by an external magnetic field.
Conventionally-fractionated image-guided intensity modulated radiotherapy (IG-IMRT): a safe and effective treatment for cancer spinal metastasis
Authors: Gong Youling , Wang Jin , Bai Sen , Jiang Xiaoqin , Xu Feng 
Published: April 2008

Abstract

Background
Treatments for cancer spinal metastasis were always palliative. This study was conducted to investigate the safety and effectiveness of IG-IMRT for these patients.

Methods
10 metastatic lesions were treated with conventionally-fractionated IG-IMRT. Daily kilovoltage cone-beam computed tomography (kV-CBCT) scan was applied to ensure accurate positioning. Plans were evaluated by the dose-volume histogram (DVH) analysis.

Results
Before set-up correction, the positioning errors in the left-right (LR), superior-inferior (SI) and anterior-posterior (AP) axes were 0.3 ± 3.2, 0.4 ± 4.5 and -0.2 ± 3.9 mm, respectively. After repositioning, those errors were 0.1 ± 0.7, 0 ± 0.8 and 0 ± 0.7 mm, respectively. The systematic/random uncertainties ranged 1.4–2.3/3.0–4.1 before and 0.1–0.2/0.7–0.8 mm after online set-up correction. In the original IMRT plans, the average dose of the planning target volume (PTV) was 61.9 Gy, with the spinal cord dose less than 49 Gy. Compared to the simulated PTVs based on the pre-correction CBCT, the average volume reduction of PTVs was 42.3% after online correction. Also, organ at risk (OAR) all benefited from CBCT-based set-up correction and had significant dose reduction with IGRT technique. Clinically, most patients had prompt pain relief within one month of treatment. There was no radiation-induced toxicity detected clinically during a median follow-up of 15.6 months.

Conclusion
IG-IMRT provides a new approach to treat cancer spinal metastasis. The precise positioning ensures the implementation of optimal IMRT plan, satisfying both the dose escalation of tumor targets and the radiation tolerance of spinal cord. It might benefit the cancer patient with spinal metastasis.
NVP-AUY922: a small molecule HSP90 inhibitor with potent antitumor activity in preclinical breast cancer models
Authors: Jensen Michael Rugaard , Schoepfer Joseph , Radimerski Thomas , Massey Andrew , Guy Chantale T , Brueggen Josef , Quadt Cornelia , Buckler Alan , Cozens Robert , Drysdale Martin J , Garcia-Echeverria Carlos , Chène Patrick 
Published: April 2008

Abstract
Introduction
Heat shock protein 90 (HSP90) is a key component of a multichaperone complex involved in the post-translational folding of a large number of client proteins, many of which play essential roles in tumorigenesis. HSP90 has emerged in recent years as a promising new target for anticancer therapies.

Methods
The concentrations of the HSP90 inhibitor NVP-AUY922 required to reduce cell numbers by 50% (GI50 values) were established in a panel of breast cancer cell lines and patient-derived human breast tumors. To investigate the properties of the compound in vivo, the pharmacokinetic profile, antitumor effect, and dose regimen were established in a BT-474 breast cancer xenograft model. The effect on HSP90-p23 complexes, client protein degradation, and heat shock response was investigated in cell culture and breast cancer xenografts by immunohistochemistry, Western blot analysis, and immunoprecipitation.

Results
We show that the novel small molecule HSP90 inhibitor NVP-AUY922 potently inhibits the proliferation of human breast cancer cell lines with GI50 values in the range of 3 to 126 nM. NVP-AUY922 induced proliferative inhibition concurrent with HSP70 upregulation and client protein depletion – hallmarks of HSP90 inhibition. Intravenous acute administration of NVP-AUY922 to athymic mice (30 mg/kg) bearing subcutaneous BT-474 breast tumors resulted in drug levels in excess of 1,000 times the cellular GI50 value for about 2 days. Significant growth inhibition and good tolerability were observed when the compound was administered once per week. Therapeutic effects were concordant with changes in pharmacodynamic markers, including HSP90-p23 dissociation, decreases in ERBB2 and P-AKT, and increased HSP70 protein levels.

Conclusion
NVP-AUY922 is a potent small molecule HSP90 inhibitor showing significant activity against breast cancer cells in cellular and in vivo settings. On the basis of its mechanism of action, preclinical activity profile, tolerability, and pharmaceutical properties, the compound recently has entered clinical phase I breast cancer trials.
Gene expression profiling in primary breast cancer distinguishes patients developing local recurrence after breast-conservation surgery, with or without postoperative radiotherapy
Authors: Niméus-Malmström Emma , Krogh Morten , Malmström Per , Strand Carina , Fredriksson Irma , Karlsson Per , Nordenskjöld Bo , Stål Olle , Östberg Görel , Peterson Carsten , Fernö Mårten 
Published: April 2008

Abstract
Introduction
Some patients with breast cancer develop local recurrence after breast-conservation surgery despite postoperative radiotherapy, whereas others remain free of local recurrence even in the absence of radiotherapy. As clinical parameters are insufficient for identifying these two groups of patients, we investigated whether gene expression profiling would add further information.

Methods
We performed gene expression analysis (oligonucleotide arrays, 26,824 reporters) on 143 patients with lymph node-negative disease and tumor-free margins. A support vector machine was employed to build classifiers using leave-one-out cross-validation.

Results
Within the estrogen receptor-positive (ER+) subgroup, the gene expression profile clearly distinguished patients with local recurrence after radiotherapy (n = 20) from those without local recurrence (n = 80 with or without radiotherapy). The receiver operating characteristic (ROC) area was 0.91, and 5,237 of 26,824 reporters had a P value of less than 0.001 (false discovery rate = 0.005). This gene expression profile provides substantially added value to conventional clinical markers (for example, age, histological grade, and tumor size) in predicting local recurrence despite radiotherapy. Within the ER- subgroup, a weaker, but still significant, signal was found (ROC area = 0.74). The ROC area for distinguishing patients who develop local recurrence from those who remain local recurrence-free in the absence of radiotherapy was 0.66 (combined ER+/ER-).

Conclusion
A highly distinct gene expression profile for patients developing local recurrence after breast-conservation surgery despite radiotherapy has been identified. If verified in further studies, this profile might be a most important tool in the decision making for surgery and adjuvant therapy.