bluuebunny/crossref_metadata_2025_split huggingface dataset:
Fatty acid synthase phosphorylation: a novel therapeutic target in HER2-overexpressing breast cancer cells
Authors: Jin Quanri , Yuan Linda X , Boulbes Delphine , Baek Jong Min , Wang Ying Nai , Gomez-Cabello Daniel , Hawke David H , Yeung Sai Ching , Lee Mong Hong , Hortobagyi Gabriel N , Hung Mien Chie , Esteva Francisco J 
Published: January 2011

Abstract
Introduction
The human epidermal growth factor receptor 2 (HER2) is a validated therapeutic target in breast cancer. Heterodimerization of HER2 with other HER family members results in enhanced tyrosine phosphorylation and activation of signal transduction pathways. HER2 overexpression increases the translation of fatty acid synthase (FASN), and FASN overexpression markedly increases HER2 signaling, which results in enhanced cell growth. However, the molecular mechanism and regulation of HER2 and FASN interaction are not well defined. Lapatinib is a small-molecule tyrosine kinase inhibitor that blocks phosphorylation of the epidermal growth factor receptor and HER2 in breast cancer cells, resulting in apoptosis. We hypothesized that FASN is directly phosphorylated by HER2, resulting in enhanced signaling and tumor progression in breast cancer cells.

Methods
Using mass spectrometry, we identified FASN as one of the proteins that is dephosphorylated by lapatinib in SKBR3 breast cancer cells. Immunofluorescence, immunoprecipitation, Western blotting, a kinase assay, a FASN enzymatic activity assay, an invasion assay, a cell viability assay and zymography were used to determine the role of FASN phosphorylation in invasion of SKBR3 and BT474 cells. The FASN inhibitor C75 and small interfering RNA were used to downregulate FASN expression and/or activity.

Results
Our data demonstrated that FASN is phosphorylated when it is in complex with HER2. FASN phosphorylation was induced by heregulin in HER2-overexpressing SKBR3 and BT474 breast cancer cells. Heregulin-induced FASN phosphorylation resulted in increased FASN enzymatic activity, which was inhibited by lapatinib. The FASN inhibitor C75 suppressed FASN activity by directly inhibiting HER2 and FASN phosphorylation. Blocking FASN phosphorylation and activity by lapatinib or C75 suppressed the activity of matrix metallopeptidase 9 and inhibited invasion of SKBR3 and BT474 cells.

Conclusions
FASN phosphorylation by HER2 plays an important role in breast cancer progression and may be a novel therapeutic target in HER2-overexpressing breast cancer cells.
An updated study-level meta-analysis of randomised controlled trials on proning in ARDS and acute lung injury
Authors: Abroug Fekri , Ouanes-Besbes Lamia , Dachraoui Fahmi , Ouanes Islem , Brochard Laurent 
Published: January 2011

Abstract
Introduction
In patients with acute lung injury (ALI) and/or acute respiratory distress syndrome (ARDS), recent randomised controlled trials (RCTs) showed a consistent trend of mortality reduction with prone ventilation. We updated a meta-analysis on this topic.

Methods
RCTs that compared ventilation of adult patients with ALI/ARDS in prone versus supine position were included in this study-level meta-analysis. Analysis was made by a random-effects model. The effect size on intensive care unit (ICU) mortality was computed in the overall included studies and in two subgroups of studies: those that included all ALI or hypoxemic patients, and those that restricted inclusion to only ARDS patients. A relationship between studies' effect size and daily prone duration was sought with meta-regression. We also computed the effects of prone positioning on major adverse airway complications.

Results
Seven RCTs (including 1,675 adult patients, of whom 862 were ventilated in the prone position) were included. The four most recent trials included only ARDS patients, and also applied the longest proning durations and used lung-protective ventilation. The effects of prone positioning differed according to the type of study. Overall, prone ventilation did not reduce ICU mortality (odds ratio = 0.91, 95% confidence interval = 0.75 to 1.2; P = 0.39), but it significantly reduced the ICU mortality in the four recent studies that enrolled only patients with ARDS (odds ratio = 0.71; 95% confidence interval = 0.5 to 0.99; P = 0.048; number needed to treat = 11). Meta-regression on all studies disclosed only a trend to explain effect variation by prone duration (P = 0.06). Prone positioning was not associated with a statistical increase in major airway complications.

Conclusions
Long duration of ventilation in prone position significantly reduces ICU mortality when only ARDS patients are considered.
Heat shock proteins and high mobility group box 1 protein lack cytokine function
Authors: Tsan Min-Fu 
Published: January 2011

ABSTRACTIn search of the etiology and pathophysiology for autoimmune and chronic inflammatory diseases, many molecules have been identified as endogenous damage-associated molecules with proinflammatory cytokine functions that may be responsible for the sterile inflammation leading to tissue injuries observed in these disorders. HSPs and HMGB1 are intracellular molecular chaperones for peptides and DNAs, respectively. They are released extracellularly upon cellular injury or activation. In vitro studies revealed that HSPs and HMGB1 were capable of inducing the release of proinflammatory cytokines by monocytes and macrophages and the activation and maturation of DCs. These cytokine effects were reported to be mediated by TLR2 and TLR4 signal transduction pathways. Thus, they were called endogenous ligands of TLR2 and TLR4 and might serve as danger signals, alarmins, or damage-associated molecules to the host immune system. It has been suggested that HSPs provide a link between innate and adaptive immune systems, and HMGB1 functions at the cross-road between innate and adaptive immunity. However, recent evidence suggests that highly purified HSPs and HMGB1, although retaining their biological activities, do not have cytokine effects. Thus, HSPs and HMGB1 do not meet the definition of endogenous ligands of TLRs, danger signals, alarmins, or damage-associated molecules. In contrast, HSPs and HMGB1 are found to bind a number of pathogen-associated molecules, such as LPS and bacterial lipopeptides, and enhance the cytokine effects of these molecules. The significance of these cytokine-enhancing effects of HSPs and HMGB1 needs further investigation.
Autumn Sonata: a film written and directed by Ingmar Bergman
Authors: Almeida Joyce 
Published: January 2011

SummaryIngmar Bergman was a Swedish director, writer and producer for film, stage and television. He directed 62 films, most of which he also wrote. Many of his films were set in the landscape of Sweden and he explored the themes of death, illness, cruelty, betrayal, mental illness, religion, and relationships between partners, children and their parents. Known as an auteur, he frequently used his film-making to examine issues from his own childhood.
Timing of menarche and depressive symptoms in adolescent girls from a UK cohort
Authors: Joinson Carol , Heron Jon , Lewis Glyn , Croudace Tim , Araya Ricardo 
Published: January 2011

BackgroundA growing number of studies suggest a link between timing of menarche and risk of depressive symptoms in adolescence, but few have prospectively examined the emergence of depressive symptoms from late childhood into adolescence.AimsTo examine whether girls who experience earlier menarche than their peers have higher levels of depressive symptoms in adolescence.MethodThe study sample comprised 2184 girls from the Avon Longitudinal Study of Parents and Children. The association between timing of menarche and depressive symptoms at 10.5, 13 and 14 years was examined within a structural equation model.ResultsGirls with early menarche (<11.5 years) had the highest level of depressive symptoms at 13 (P = 0.007) and 14 years (P<0.001) compared with those with normative and late timing of menarche.ConclusionsEarly maturing girls are at increased risk of depressive symptoms in adolescence and could be targeted by programmes aimed at early intervention and prevention.
The smoking culture in psychiatry: time for change
Authors: Ratschen Elena , Britton John , McNeill Ann 
Published: January 2011

SummarySmoking is closely linked to severe mental illness and has a major detrimental impact on individuals' lives. Despite this and the recent societal ‘de-normalisation’ of smoking, the historic ‘smoking culture’ still prevails within mental health settings. Change is urgently required to prevent a widening of existing health gaps.
Eating disorders, DSM–5 and clinical reality
Authors: Fairburn Christopher G. , Cooper Zafra 
Published: January 2011

SummaryThe DSM–IV scheme for classifying eating disorders is a poor reflection of clinical reality. In adults it recognises two conditions, anorexia nervosa and bulimia nervosa, yet these states are merely two presentations among many. As a consequence, at least half the cases seen in clinical practice are relegated to the residual diagnosis ‘eating disorder not otherwise specified’. The changes proposed for DSM–5 will only partially succeed in correcting this shortcoming. With DSM–6 in mind, it is clear that comprehensive transdiagnostic samples need to be studied with data collected on their current state, course and response to treatment. Only with such data will it be possible to derive an empirically based classificatory scheme that is both rooted in clinical reality and of value to clinicians.
Nidotherapy in the treatment of substance misuse, psychosis and personality disorder: secondary analysis of a controlled trial
Authors: Tyrer Peter , Milošeska Katarina , Whittington Craig , Ranger Maja , Khaleel Ibrahim , Crawford Mike , North Bernard , Barrett Barbara 
Published: January 2011

Aims and methodTo examine the clinical outcome and bed usage in patients with comorbid substance misuse and psychosis. The patients were randomised to ordinary assertive outreach team care or to enhanced assertive outreach with nidotherapy. Ratings of clinical symptoms, social function, engagement with services, bed usage (primary outcome after 1 year) and economic costs were assessed at baseline and at 6 and 12 months after randomisation.ResultsPatients referred to nidotherapy had similar reduction in symptoms and engagement, with marginal superiority in social function (P= 0.045). There was a 110% reduction in hospital bed use after 1 year compared with control assertive care (P= 0.03). The mean cost savings for each patient allocated to nidotherapy was £14705 per year, mainly as a consequence of reduced psychiatric bed use.Clinical implicationsNidotherapy shows promise in the treatment of substance misuse and psychosis and may reduce hospital bed usage.
Leptin-Independent Programming of Adult Body Weight and Adiposity in Mice
Authors: Cottrell Elizabeth C. , Martin-Gronert Malgorzata S. , Fernandez-Twinn Denise S. , Luan Jian'an , Berends Lindsey M. , Ozanne Susan E. 
Published: January 2011

Abstract
Low birth weight and rapid postnatal weight gain are independent and additive risk factors for the subsequent development of metabolic disease. Despite an abundance of evidence for these associations, mechanistic data are lacking. The hormone leptin has received significant interest as a potential programming factor, because differences in the profile of leptin in early life have been associated with altered susceptibility to obesity. Whether leptin alone is a critical factor for programming obesity has, until now, remained unclear. Using the leptin-deficient ob/ob mouse, we show that low birth weight followed by rapid catch-up growth during lactation (recuperated offspring) leads to a persistent increase in body weight in adult life, both in wild-type and ob/ob animals. Furthermore, recuperated offspring are hyperphagic and epididymal fat pad weights are significantly increased, reflecting greater adiposity. These results show definitively that factors other than leptin are crucial in the programming of energy homeostasis in this model and are powerful enough to alter adiposity in a genetically obese strain.
Glutamine Triggers and Potentiates Glucagon-Like Peptide-1 Secretion by Raising Cytosolic Ca2+ and cAMP
Authors: Tolhurst Gwen , Zheng Yue , Parker Helen E. , Habib Abdella M. , Reimann Frank , Gribble Fiona M. 
Published: January 2011

Abstract
L-glutamine stimulates glucagon-like peptide 1 (GLP-1) secretion in human subjects and cell lines. As recent advances have enabled the study of primary GLP-1–releasing L cells, this study aimed to characterize glutamine-sensing pathways in native murine L cells. L cells were identified using transgenic mice with cell-specific expression of fluorescent markers. Cells were studied in primary colonic cultures from adult mice, or purified by flow cytometry for expression analysis. Intracellular Ca2+ was monitored in cultures loaded with Fura2, and cAMP was studied using Förster resonance energy transfer sensors expressed in GLUTag cells. Asparagine, phenylalanine, and glutamine (10 mm) triggered GLP-1 release from primary cultures, but glutamine was the most efficacious, increasing secretion 1.9-fold with an EC50 of 0.19 mm. Several amino acids triggered Ca2+ changes in L cells, comparable in magnitude to that induced by glutamine. Glutamine-induced Ca2+ responses were abolished in low Na+ solution and attenuated in Ca2+ free solution, suggesting a role for Na+ dependent uptake and Ca2+ influx. The greater effectiveness of glutamine as a secretagogue was paralleled by its ability to increase cAMP in GLUTag cells. Glutamine elevated intracellular cAMP to 36% of that produced by a maximal stimulus, whereas asparagine only increased intracellular cAMP by 24% and phenylalanine was without effect. Glutamine elevates both cytosolic Ca2+ and cAMP in L cells, which may account for the effectiveness of glutamine as a GLP-1 secretagogue. Therapeutic agents like glutamine that target synergistic pathways in L cells might play a future role in the treatment of type 2 diabetes.
Comparison between Surrogate Indexes of Insulin Sensitivity/Resistance and Hyperinsulinemic Euglycemic Glucose Clamps in Rhesus Monkeys
Authors: Lee Ho-Won , Muniyappa Ranganath , Yan Xu , Yue Lilly Q. , Linden Ellen H. , Chen Hui , Hansen Barbara C. , Quon Michael J. 
Published: January 2011

Abstract
The euglycemic glucose clamp is the reference method for assessing insulin sensitivity in humans and animals. However, clamps are ill-suited for large studies because of extensive requirements for cost, time, labor, and technical expertise. Simple surrogate indexes of insulin sensitivity/resistance including quantitative insulin-sensitivity check index (QUICKI) and homeostasis model assessment (HOMA) have been developed and validated in humans. However, validation studies of QUICKI and HOMA in both rats and mice suggest that differences in metabolic physiology between rodents and humans limit their value in rodents. Rhesus monkeys are a species more similar to humans than rodents. Therefore, in the present study, we evaluated data from 199 glucose clamp studies obtained from a large cohort of 86 monkeys with a broad range of insulin sensitivity. Data were used to evaluate simple surrogate indexes of insulin sensitivity/resistance (QUICKI, HOMA, Log HOMA, 1/HOMA, and 1/Fasting insulin) with respect to linear regression, predictive accuracy using a calibration model, and diagnostic performance using receiver operating characteristic. Most surrogates had modest linear correlations with SIClamp (r ≈ 0.4–0.64) with comparable correlation coefficients. Predictive accuracy determined by calibration model analysis demonstrated better predictive accuracy of QUICKI than HOMA and Log HOMA. Receiver operating characteristic analysis showed equivalent sensitivity and specificity of most surrogate indexes to detect insulin resistance. Thus, unlike in rodents but similar to humans, surrogate indexes of insulin sensitivity/resistance including QUICKI and log HOMA may be reasonable to use in large studies of rhesus monkeys where it may be impractical to conduct glucose clamp studies.
Independent and Combined Effects of Calcium-Vitamin D3 and Exercise on Bone Structure and Strength in Older Men: An 18-Month Factorial Design Randomized Controlled Trial
Authors: Kukuljan Sonja , Nowson Caryl A. , Sanders Kerrie M. , Nicholson Geoff C. , Seibel Markus J. , Salmon Jo , Daly Robin M. 
Published: January 2011

Abstract

Context:
Exercise and calcium-vitamin D are independently recognized as important strategies to prevent osteoporosis, but their combined effects on bone strength and its determinants remain uncertain.

Objective:
To assess whether calcium-vitamin D3 fortified milk could enhance the effects of exercise on bone strength, structure, and mineral density in middle-aged and older men.

Design, Setting, Participants:
An 18-month factorial design randomized controlled trial in which 180 men aged 50–79 years were randomized to the following: exercise + fortified milk; exercise; fortified milk; or controls. Exercise consisted of progressive resistance training with weight-bearing impact activities performed 3 d/week. Men assigned to fortified milk consumed 400 ml/d of 1% fat milk containing 1000 mg/d calcium and 800 IU/d vitamin D3.

Main Outcome Measures:
Changes in bone mineral density (BMD), bone structure, and strength at the lumbar spine (LS), proximal femur, mid-femur, and mid-tibia measured by dual energy x-ray absorptiometry and/or quantitative computed tomography.

Results:
There were no exercise-by-fortified milk interactions at any skeletal site. Main effect analysis showed that exercise led to a 2.1% (95% confidence interval, 0.5–3.6) net gain in femoral neck section modulus, which was associated with an approximately 1.9% gain in areal BMD and cross-sectional area. Exercise also improved LS trabecular BMD [net gain 2.2% (95% confidence interval, 0.2–4.1)], but had no effect on mid-femur or mid-tibia BMD, structure, or strength. There were no main effects of the fortified milk at any skeletal site.

Conclusion:
A community-based multi-component exercise program successfully improved LS and femoral neck BMD and strength in healthy older men, but providing additional calcium-vitamin D3 to these replete men did not enhance the osteogenic response.
GLP-1 and Calcitonin Concentration in Humans: Lack of Evidence of Calcitonin Release from Sequential Screening in over 5000 Subjects with Type 2 Diabetes or Nondiabetic Obese Subjects Treated with the Human GLP-1 Analog, Liraglutide
Authors: Hegedüs Laszlo , Moses Alan C. , Zdravkovic Milan , Le Thi Tu , Daniels Gilbert H. 
Published: January 2011

Background:
Serum calcitonin (CT) is a well-accepted marker of C-cell proliferation, particularly in medullary thyroid carcinoma. Chronic glucagon-like peptide-1 (GLP-1) receptor agonist administration in rodents has been associated with increased serum CT levels and C-cell tumor formation. There are no longitudinal studies measuring CT in humans without medullary thyroid carcinoma or a family history of medullary thyroid carcinoma and no published studies on the effect of GLP-1 receptor agonists on human serum CT concentrations.

Aim:
The aim of the study was to determine serum CT response over time to the GLP-1 receptor agonist liraglutide in subjects with type 2 diabetes mellitus or nondiabetic obese subjects.

Methods:
Unstimulated serum CT concentrations were measured at 3-month intervals for no more than 2 yr in a series of trials in over 5000 subjects receiving liraglutide or control therapy.

Results:
Basal mean CT concentrations were at the low end of normal range in all treatment groups and remained low throughout the trials. At 2 yr, estimated geometric mean values were no greater than 1.0 ng/liter, well below upper normal ranges for males and females. Proportions of subjects whose CT levels increased above a clinically relevant cutoff of 20 ng/liter were very low in all groups. There was no consistent dose or time-dependent relationship and no consistent difference between treatment groups.

Conclusions:
These data do not support an effect of GLP-1 receptor activation on serum CT levels in humans and suggest that findings previously reported in rodents may not apply to humans. However, the long-term consequences of GLP-1 receptor agonist treatment are a subject of further studies.
Experimental and Numerical Study of the Effect of an Oversize Particle on the Shear Strength of Mined-Rock Pile Material
Authors: Fakhimi Ali , Hosseinpour Hooman 
Published: January 2011

AbstractDuring in situ direct shear testing on the Questa mined-rock pile material, oversize rock fragments were encountered in the shear box. To study the effect of an oversize particle on the measured friction angles and cohesions, both laboratory and numerical direct shear tests were conducted on unsaturated samples of the rock pile material. In the numerical simulation, a hybrid discrete-finite element method was implemented in which the rock pile material was modeled with discrete particles while the shear box was modeled with finite elements. Both the numerical and physical tests suggest an increase in the measured shear strength of the material due to the presence of an oversize particle in the box. More specifically, the presence of an oversize particle causes an increase in friction angle while cohesion in most situations decreases. The location of the oversize particle along the shear plane was found to be important, as it can modify the failure mechanism.
Association Between Sexually Transmitted Diseases and Young Adults' Self-reported Abstinence
Authors: DiClemente Ralph J. , Sales Jessica McDermott , Danner Fred , Crosby Richard A. 
Published: January 2011

OBJECTIVE:
Self-reported behavior has been the cornerstone of sexual health research and clinical practice, yet advances in sexually transmitted disease (STD) screening provide researchers with the opportunity to objectively quantify sexual risk behaviors. However, the extent to which young adults' laboratory-confirmed STD results and self-reported sexual behaviors are consistent has not been assessed in a nationally representative sample.

PATIENTS AND METHODS:
Data are derived from participants who completed wave 3 in the National Longitudinal Study of Adolescent Health. Young adults (N = 14 012) completed an audio computer-assisted self-interviewing survey and provided a urine specimen to detect the presence of Chlamydia trachomatis and Neisseria gonorrhoeae, and a polymerase chain reaction assay to detect Trichomonas vaginalis.

RESULTS:
More than 10% of young adults with a laboratory-confirmed positive STD result reported abstaining from sexual intercourse in the 12 months before assessment and STD testing. After controlling for several sociodemographic factors, self-reported sex (versus those who reported abstinence) in the previous 12 months was significantly associated with testing positive, but the odds of testing positive were only slightly more than twofold (adjusted odds ratio: 2.11 [95% confidence interval: 2.097–2.122]).

CONCLUSIONS:
Findings indicate discrepancy between young adults' positive STD status and self-reported sexual behavior. No significant correlates of discrepant reporting were identified. From a clinical standpoint, the discrepancies between STD positivity and self-reported sexual behavior observed in this nationally representative sample suggest that routine STD screening may be beneficial and necessary to reduce STD morbidity among young adults.