bluuebunny/crossref_metadata_2025 huggingface dataset:
Predicting the Restenosis Benefit of Drug-Eluting Versus Bare Metal Stents in Percutaneous Coronary Intervention
Authors: Yeh Robert W. , Normand Sharon-Lise T. , Wolf Robert E. , Jones Philip G. , Ho Kalon K.L. , Cohen David J. , Cutlip Donald E. , Mauri Laura , Kugelmass Aaron D. , Amin Amit P. , Spertus John A.
Published: September 2011

Background—

Drug-eluting stents (DES) for percutaneous coronary intervention decrease the risk of restenosis compared with bare metal stents. However, they are costlier, require prolonged dual antiplatelet therapy, and provide the most benefit in patients at highest risk for restenosis. To assist physicians in targeting DES use in patients at the highest risk for target vessel revascularization (TVR), we developed and validated a model to predict TVR.

Methods and Results—

Preprocedural clinical and angiographic data from 27 107 percutaneous coronary intervention hospitalizations between October 1, 2004, and September 30, 2007, in Massachusetts were used to develop prediction models for TVR at 1 year. Models were developed from a two-thirds random sample and validated in the remaining third. The overall rate of TVR was 7.6% (6.7% with DES, 11% with bare metal stents). Significant predictors of TVR included prior percutaneous coronary intervention, emergency or salvage percutaneous coronary intervention, prior coronary bypass surgery, peripheral vascular disease, diabetes mellitus, and angiographic characteristics. The model was superior to a 3-variable model of diabetes mellitus, stent diameter, and stent length (c statistic, 0.66 versus 0.60;
P
<0.001) and was well calibrated. The predicted number needed to treat with DES to prevent 1 TVR compared with bare metal stents ranged from 6 (95% confidence interval, 5.4–7.6) to 80 (95% confidence interval, 62.7–116.3), depending on patients' clinical and angiographic factors.

Conclusions—

A predictive model using commonly collected variables can identify patients who may derive the greatest benefit in TVR reduction from DES. Whether use of the model improves the safety and cost-effectiveness of DES use should be tested prospectively.
Exercise Training Alters the Balance Between Vasoactive Compounds in Skeletal Muscle of Individuals With Essential Hypertension
Authors: Hansen Ane H. , Nyberg Michael , Bangsbo Jens , Saltin Bengt , Hellsten Ylva
Published: September 2011

The effects of physical training on the formation of vasodilating and vasoconstricting compounds, as well as on related proteins important for vascular function, were examined in skeletal muscle of individuals with essential hypertension (n=10). Muscle microdialysis samples were obtained from subjects with hypertension before and after 16 weeks of physical training. Muscle dialysates were analyzed for thromboxane A
2
, prostacyclin, nucleotides, and nitrite/nitrate. Protein levels of thromboxane synthase, prostacyclin synthase, cyclooxygenase 1 and 2, endothelial nitric oxide synthase (eNOS), cystathionine-γ-lyase, cytochrome P450 4A and 2C9, and the purinergic receptors P2X1 and P2Y2 were determined in skeletal muscle. The protein levels were compared with those of normotensive control subjects (n=12). Resting muscle dialysate thromboxane A
2
and prostacyclin concentrations were lower (
P
<0.05) after training compared with before training. Before training, dialysate thromboxane A
2
decreased with acute exercise, whereas after training, no changes were found. Before training, dialysate prostacyclin levels did not increase with acute exercise, whereas after training there was an 82% (
P
<0.05) increase from rest to exercise. The exercise-induced increase in ATP and ADP was markedly reduced after training (
P
<0.05). The amount of eNOS protein in the hypertensive subjects was 40% lower (
P
<0.05) than in the normotensive control subjects, whereas cystathionine-γ-lyase levels were 25% higher (
P
<0.05), potentially compensating for the lower eNOS level. We conclude that exercise training alters the balance between vasodilating and vasoconstricting compounds as evidenced by a decrease in the level of thromboxane, reduction in the exercise-induced increase in ATP and a greater exercise-induced increase in prostacyclin.
Impact of Resistance Training on Blood Pressure and Other Cardiovascular Risk Factors
Authors: Cornelissen Véronique A. , Fagard Robert H. , Coeckelberghs Ellen , Vanhees Luc
Published: September 2011

We reviewed the effect of resistance training on blood pressure and other cardiovascular risk factors in adults. Randomized, controlled trials lasting ≥4 weeks investigating the effects of resistance training on blood pressure in healthy adults (age ≥18 years) and published in a peer-reviewed journal up to June 2010 were included. Random- and fixed-effects models were used for analyses, with data reported as weighted means and 95% confidence limits. We included 28 randomized, controlled trials, involving 33 study groups and 1012 participants. Overall, resistance training induced a significant blood pressure reduction in 28 normotensive or prehypertensive study groups [−3.9 (−6.4; −1.2)/−3.9 (−5.6; −2.2) mm Hg], whereas the reduction [−4.1 (−0.63; +1.4)/−1.5 (−3.4; +0.40) mm Hg] was not significant for the 5 hypertensive study groups. When study groups were divided according to the mode of training, isometric handgrip training in 3 groups resulted in a larger decrease in blood pressure [−13.5 (−16.5; −10.5)/−6.1(−8.3; −3.9) mm Hg] than dynamic resistance training in 30 groups [−2.8 (−4.3; −1.3)/−2.7 (−3.8; −1.7) mm Hg]. After dynamic resistance training, V
o
2
peak increased by 10.6% (
P
=0.01), whereas body fat and plasma triglycerides decreased by 0.6% (
P
<0.01) and 0.11 mmol/L (
P
<0.05), respectively. No significant effect could be observed on other blood lipids and fasting blood glucose. This meta-analysis supports the blood pressure–lowering potential of dynamic resistance training and isometric handgrip training. In addition, dynamic resistance training also favorably affects some other cardiovascular risk factors. Our results further suggest that isometric handgrip training may be more effective for reducing blood pressure than dynamic resistance training. However, given the small amount of isometric studies available, additional studies are warranted to confirm this finding.
Silencing of Hypoxia-Inducible Factor-1α Gene Attenuated Angiotensin II–Induced Renal Injury in Sprague-Dawley Rats
Authors: Zhu Qing , Wang Zhengchao , Xia Min , Li Pin-Lan , Van Tassell Benjamin W. , Abbate Antonio , Dhaduk Romesh , Li Ningjun
Published: September 2011

Although it has been shown that upregulation of hypoxia-inducible factor (HIF)-1α is protective in acute ischemic renal injury, long-term overactivation of HIF-1α is implicated to be injurious in chronic kidney diseases. Angiotensin II (Ang II) is a well-known pathogenic factor producing chronic renal injury and has also been shown to increase HIF-1α. However, the contribution of HIF-1α to Ang II–induced renal injury has not been evidenced. The present study tested the hypothesis that HIF-1α mediates Ang II–induced renal injury in Sprague-Dawley rats. Chronic renal injury was induced by Ang II infusion (200 ng/kg per minute) for 2 weeks in uninephrectomized rats. Transfection of vectors expressing HIF-1α small hairpin RNA into the kidneys knocked down HIF-1α gene expression by 70%, blocked Ang II–induced HIF-1α activation, and significantly attenuated Ang II–induced albuminuria, which was accompanied by inhibition of Ang II–induced vascular endothelial growth factor, a known glomerular permeability factor, in glomeruli. HIF-1α small hairpin RNA also significantly improved the glomerular morphological damage induced by Ang II. Furthermore, HIF-1α small hairpin RNA blocked Ang II–induced upregulation of collagen and α-smooth muscle actin in tubulointerstitial region. There was no difference in creatinine clearance and Ang II–induced increase in blood pressure. HIF-1α small hairpin RNA had no effect on Ang II–induced reduction in renal blood flow and hypoxia in the kidneys. These data suggested that overactivation of HIF-1α–mediated gene regulation in the kidney is a pathogenic pathway mediating Ang II–induced chronic renal injuries, and normalization of overactivated HIF-1α may be used as a treatment strategy for chronic kidney damages associated with excessive Ang II.
Reflections on the Opportunities and Challenges of Disaster Response
Authors: Juntunen Cindy L.
Published: September 2011

This reaction article applauds the authors of the Major Contribution for their thoughtful and thorough consideration of the myriad issues that accompany disaster mental health work. The reaction highlights three themes that emerged in the articles of the contribution: opportunities for collaboration, opportunities for the application of social justice, and opportunities for bioecological research and interventions. In addition, suggestions are made for future exploration of prevention opportunities, separating the reality of disaster response from popular media images, and ethical considerations for counseling psychologists working as disaster responders.
Toward an Organizational Model of Change in Elementary Schools
Authors: Schechter Chen , Qadach Mowafaq
Published: September 2011

Purpose: This study explored a theoretical model that links teachers’ perceived uncertainty and teachers’ sense of collective efficacy with organizational learning mechanisms (OLMs) in elementary schools. OLMs serve as a mediator construct. Research Design: For testing the primary theoretical model, 801 teachers from 61 elementary schools (33 urban and 28 suburban) in Israel’s largest district responded to the research instruments. The authors used structural equation modeling to determine whether OLMs mediate between teachers’ perceived uncertainty and their sense of collective efficacy. Findings: A significant model, which included direct and indirect effects of teachers’ perceived uncertainty on teachers’ sense of collective efficacy, emerged for the urban school context. Although OLMs (storing, retrieving, and putting to use of information) served as a prominent mediating variable in the urban school context, OLMs did not play a mediating role in the research model for the suburban school context. Conclusions: This study strengthens the feasibility of the OLMs framework, based on information processing, to provide a concrete description of organizational learning processes in schools. The study provides a deeper understanding of how OLMs can serve as a significant link between the dynamic school environment and teachers’ attitudes, which may ultimately improve teachers’ work and students’ learning.
Severe Cases of Pandemic H1N1 Pneumonia and Respiratory Failure Requiring Intensive Care
Authors: Lam Julie , Nikhanj Nidhi , Ngab Tarik , Tennant Richard , Shahedi Kamyar , Mathisen Glenn , Donovan Suzanne , Kamangar Nader
Published: September 2011

Background: The objective of our study is to analyze the clinical data of patients with pandemic H1N1 2009 infection admitted to the intensive care unit (ICU) and to report key features observed among these patients. Methods: A total of 18 patients were admitted to our ICU between July and November 2009, with a primary diagnosis of influenza. Clinical data were analyzed to identify potential risk factors and characteristics thought to affect outcomes. Results: Our patients were between ages 23 and 62 (mean 41). In all, 10 were obese. Two had no other comorbid conditions and 6 had obesity as their only comorbid condition. The most common symptoms were fever, shortness of breath, and cough. Laboratory data were notable for elevated creatine kinase levels, transaminitis, and lack of leukocytosis. The rapid influenza detection test (RIDT) had a 76% false negative result. Patients with a negative RIDT had their infection confirmed with real-time reverse transcriptase polymerase chain reaction (rRT-PCR). A total of 12 patients required invasive mechanical ventilation, with over half of whom responded only to nonconventional modes of ventilation. Most patients received high-dose (150 mg twice daily) oseltamivir. In all, 3 patients died and 11 were discharged without any long-term sequalae. Conclusions: Unlike seasonal influenza, our patients were not in the extremes of age. Most were obese and presented with severe respiratory distress and hypoxia in the summer months. A negative RIDT did not exclude pandemic H1N1 2009. Using a higher dose of oseltamivir and nonconventional modes of ventilation may have improved the outcome in our subset of patients. Hence, patients with a high clinical suspicion of severe influenza infection should be treated early and aggressively, even before confirmatory results are available.
Theoretical and experimental studies on the noise control of centrifugal fans combining absorbing liner and inclined tongue
Authors: Gu Y , Qi D , Mao Y , Wang X
Published: September 2011

In previous work, it has been validated that the inclined tongue has a significant effect on controlling the tonal noise of centrifugal fans. In order to reduce the broadband noise of centrifugal fans, theoretical and experimental research studies have been implemented to study the effect of the sound-absorption volute on noise propagation. First, a mathematical–physical model of the sound-absorption volute is established to explore the influence of the sound-absorption coefficient of the liner, which is dependent on the liner thickness, cavity depth, etc. Then, an experimental study is carried out to measure the coupling effect between the absorbing liner and the inclined tongue and its potential for the noise control of centrifugal fans. The experimental results agree well with the theoretical result, and validate the mathematical–physical model, proving it a practical model for further optimization of the sound-absorption volute. In addition, the results indicate that considerable noise reduction can be achieved by combining both the posed absorbing liner and modified inclined tongue.
Iran’s Quest for Nuclear Weapon Status
Authors: Mahapatra Chintamani , Tourangbam Monish
Published: September 2011

In recent times, US policy towards Iran’s nuclear ambition has become one of the most contested and hotly debated issues in the US and elsewhere. As the Bush administration ended with little tangible success in addressing the proliferation concerns involving Iran, the issue has come to hunt the Obama administration as well. The American strategic community largely agrees that Iran has the ambition to acquire nuclear weapon status and thus the debate revolves around how best to respond to it. Vigorous arguments have been paraded to assess the cost and benefits of a US pre-emptive strike against Iran’s nuclear installations. Similar and equally vital deliberations abound in the strategic circles with respect to the option of an Israeli strike and its implication for US foreign policy. The article attempts to analyse this dynamic American debate at a critical juncture as President Obama, previously seen as the anti-thesis of the Bush era, seems to be facing the same sort of constraints that his predecessor was up against, while searching for a sound policy to deal with the Iranian conundrum.
Mortal love: Care practices in animal experimentation
Authors: Holmberg Tora
Published: September 2011

This article addresses the embodied nature of laboratory human—animal practices in order to understand the notions of care that take place within an institution of domination — the apparatus of animal experimentation. How is it possible to both love and harm in this context? Building on animal studies and feminist ethics, the theme of emotionality is explored in the section ‘loving animals’. Here it is demonstrated that empathy and affection for individual animals, as well as species, are strong components of an experimental ethos expressed by the informants. The second empirical section deals with the issue of ‘killing well’. The good kill is supposed to be done with care: quickly and compassionately. This is performed by way of bodily measures of care, technological refinement and personal skills and, sometimes, with the help of a division of labour. In the concluding section, the empirical findings are read through the framework, where the feminist theoretical analysis of love, dependency and care from an embodiment perspective understands the dialectics of instrumentalisation and exploitation of — and care for — animals, not as something that goes on above or outside of relations, but rather as something that can be understood from within. ‘Mortal love’ is the attempt to capture and theorise this dialectic, arguing that emotions of love and friendship are not mere justifications for the harm and killing performed, but rather intrinsic dimensions of the embodied animaling of experimental human—animal relations.
Body Worlds’ plastinates, the human/nonhuman interface, and feminism
Authors: Scott Rebecca
Published: September 2011

Body Worlds is a hugely popular exhibition that claims to offer a reverential and educational experience of the ‘real human body’ through the display of plastinated dead human bodies. However, because they are posed, staged, and composed of significant nonhuman artifice, plastinates are ambivalently ‘real’ as human bodies, let alone ‘real’ as humans. Plastinates are as much nonhuman as human, and neither category fully accounts for them. In this article, I discuss the consequences of this for feminist theory. Approaches in feminist theory that reify, either implicitly or explicitly, a human/nonhuman binary framework are challenged by plastinates. I show that locating plastinates within either ontological category, though not fully accounting for them, enables feminist critiques of the exhibition; however, these categories also paradoxically permit forms of violence with which feminists are typically concerned. In this way, I argue that plastinates force feminist thought to the very interface of the human/nonhuman divide. When applied to Body Worlds, these concepts at best form a heuristic ontological hinge whose angle is determined by ethical and political commitments, illustrating the ways in which key ontologies should be seen as political strategies more or less amenable to feminist goals, but not more or less true. I argue that what lies at the crux of this hinge, in the case of plastinates, is death, and suggest that Body Worlds demands that the interface of death with life become a key feminist concern.
A Grateful Heart is a Nonviolent Heart
Authors: DeWall C. Nathan , Lambert Nathaniel M. , Pond Richard S. , Kashdan Todd B. , Fincham Frank D.
Published: September 2011

Five studies tested the hypothesis that gratitude is linked to lower levels of aggression. Although gratitude increases mental well-being, it is unknown whether gratitude mitigates against aggression. Gratitude motivates people to express sensitivity and concern for others and stimulates prosocial behavior. Aggression, defined as intentionally harming another person who is motivated to avoid the harm, runs counter to the motivation to increase others’ welfare and should be reduced among grateful people. Cross-sectional, longitudinal, experience sampling, and experimental designs yielded converging evidence to show that gratitude is linked to lower aggression. Higher empathy mediated the relationship between gratitude and lower aggression. These findings have widespread applications for understanding the role of emotion on aggression and can inform interventions aimed at reducing interpersonal aggression.
Genome-wide ChIP-Seq reveals a dramatic shift in the binding of the transcription factor erythroid Kruppel-like factor during erythrocyte differentiation
Authors: Pilon Andre M. , Ajay Subramanian S. , Kumar Swathi Ashok , Steiner Laurie A. , Cherukuri Praveen F. , Wincovitch Stephen , Anderson Stacie M. ,   NISC Comparative Sequencing Center, Mullikin James C. , Gallagher Patrick G. , Hardison Ross C. , Margulies Elliott H. , Bodine David M.
Published: September 2011

Erythropoiesis is dependent on the activity of transcription factors, including the erythroid-specific erythroid Kruppel-like factor (EKLF). ChIP followed by massively parallel sequencing (ChIP-Seq) is a powerful, unbiased method to map trans-factor occupancy. We used ChIP-Seq to study the interactome of EKLF in mouse erythroid progenitor cells and more differentiated erythroblasts. We correlated these results with the nuclear distribution of EKLF, RNA-Seq analysis of the transcriptome, and the occupancy of other erythroid transcription factors. In progenitor cells, EKLF is found predominantly at the periphery of the nucleus, where EKLF primarily occupies the promoter regions of genes and acts as a transcriptional activator. In erythroblasts, EKLF is distributed throughout the nucleus, and erythroblast-specific EKLF occupancy is predominantly in intragenic regions. In progenitor cells, EKLF modulates general cell growth and cell cycle regulatory pathways, whereas in erythroblasts EKLF is associated with repression of these pathways. The EKLF interactome shows very little overlap with the interactomes of GATA1, GATA2, or TAL1, leading to a model in which EKLF directs programs that are independent of those regulated by the GATA factors or TAL1.
A cell factory of Bacillus subtilis engineered for the simple bioconversion of myo-inositol to scyllo-inositol, a potential therapeutic agent for Alzheimer's disease
Authors: Yamaoka Masaru , Osawa Shin , Morinaga Tetsuro , Takenaka Shinji , Yoshida Ken-ichi
Published: September 2011

Background

A stereoisomer of inositol, scyllo-inositol, is known as a promising therapeutic agent for Alzheimer's disease, since it prevents the accumulation of beta-amyloid deposits, a hallmark of the disease. However, this compound is relatively rare in nature, whereas another stereoisomer of inositol, myo-inositol, is abundantly available.

Results

Bacillus subtilis possesses a unique inositol metabolism involving both stereoisomers. We manipulated the inositol metabolism in B. subtilis to permit the possible bioconversion from myo-inositol to scyllo-inositol. Within 48 h of cultivation, the engineered strain was able to convert almost half of 10 g/L myo-inositol to scyllo-inositol that accumulated in the culture medium.

Conclusions

The engineered B. subtilis serves as a prototype of cell factory enabling a novel and inexpensive supply of scyllo-inositol.
c-Myc dependent expression of pro-apoptotic Bim renders HER2-overexpressing breast cancer cells dependent on anti-apoptotic Mcl-1
Authors: Campone Mario , Noël Bélinda , Couriaud Cécile , Grau Morgan , Guillemin Yannis , Gautier Fabien , Gouraud Wilfried , Charbonnel Catherine , Campion Loïc , Jézéquel Pascal , Braun Frédérique , Barré Benjamin , Coqueret Olivier , Barillé-Nion Sophie , Juin Philippe
Published: September 2011

Background

Anti-apoptotic signals induced downstream of HER2 are known to contribute to the resistance to current treatments of breast cancer cells that overexpress this member of the EGFR family. Whether or not some of these signals are also involved in tumor maintenance by counteracting constitutive death signals is much less understood. To address this, we investigated what role anti- and pro-apoptotic Bcl-2 family members, key regulators of cancer cell survival, might play in the viability of HER2 overexpressing breast cancer cells.

Methods

We used cell lines as an in vitro model of HER2-overexpressing cells in order to evaluate how anti-apoptotic Bcl-2, Bcl-xL and Mcl-1, and pro-apoptotic Puma and Bim impact on their survival, and to investigate how the constitutive expression of these proteins is regulated. Expression of the proteins of interest was confirmed using lysates from HER2-overexpressing tumors and through analysis of publicly available RNA expression data.

Results

We show that the depletion of Mcl-1 is sufficient to induce apoptosis in HER2-overexpressing breast cancer cells. This Mcl-1 dependence is due to Bim expression and it directly results from oncogenic signaling, as depletion of the oncoprotein c-Myc, which occupies regions of the Bim promoter as evaluated in ChIP assays, decreases Bim levels and mitigates Mcl-1 dependence. Consistently, a reduction of c-Myc expression by inhibition of mTORC1 activity abrogates occupancy of the Bim promoter by c-Myc, decreases Bim expression and promotes tolerance to Mcl-1 depletion. Western blot analysis confirms that naïve HER2-overexpressing tumors constitutively express detectable levels of Mcl-1 and Bim, while expression data hint on enrichment for Mcl-1 transcripts in these tumors.

Conclusions

This work establishes that, in HER2-overexpressing tumors, it is necessary, and maybe sufficient, to therapeutically impact on the Mcl-1/Bim balance for efficient induction of cancer cell death.
A reaction-diffusion model of the receptor-toxin-antibody interaction
Authors: Skakauskas Vladas , Katauskis Pranas , Skvortsov Alex
Published: September 2011

Background

It was recently shown that the treatment effect of an antibody can be described by a consolidated parameter which includes the reaction rates of the receptor-toxin-antibody kinetics and the relative concentration of reacting species. As a result, any given value of this parameter determines an associated range of antibody kinetic properties and its relative concentration in order to achieve a desirable therapeutic effect. In the current study we generalize the existing kinetic model by explicitly taking into account the diffusion fluxes of the species.

Results

A refined model of receptor-toxin-antibody (RTA) interaction is studied numerically. The protective properties of an antibody against a given toxin are evaluated for a spherical cell placed into a toxin-antibody solution. The selection of parameters for numerical simulation approximately corresponds to the practically relevant values reported in the literature with the significant ranges in variation to allow demonstration of different regimes of intracellular transport.

Conclusions

The proposed refinement of the RTA model may become important for the consistent evaluation of protective potential of an antibody and for the estimation of the time period during which the application of this antibody becomes the most effective. It can be a useful tool for in vitro selection of potential protective antibodies for progression to in vivo evaluation.
Giant right coronary artery aneurysm presenting with non-ST elevation myocardial infarction and severe mitral regurgitation: a case report
Authors: Nazareth Justin , Weinberg Laurence , Fernandes Jon , Peyton Phil , Seevanayagam Sivan
Published: September 2011

Introduction

Coronary artery aneurysms are seen in 1.5-5% of patients presenting for coronary angiography, but giant aneurysms, defined as being greater than 2 cm in diameter, are rare. Given the paucity of cases and limited experience in diagnosis and management of the disease, each case is a learning tool in itself.

Case presentation

We report the rare case of a 78-year-old Caucasian man who presented to a peripheral emergency department with chest pain and was subsequently found to have a giant right coronary artery aneurysm. Following initial investigation and treatment he was referred to our hospital for definitive management.

Conclusion

The case described illustrates one of the varied presentations and subsequent management of an ill-defined and heterogeneous disease process. Given the limited experience with giant aneurysms in the coronary circulation, this case provides valuable insight into the clinical presentation of the disease and gives an example of the management of the most recent such case at our hospital.
Serum Enterolactone and Prognosis of Postmenopausal Breast Cancer
Authors: Buck Katharina , Vrieling Alina , Zaineddin Aida Karina , Becker Susen , Hüsing Anika , Kaaks Rudolf , Linseisen Jakob , Flesch-Janys Dieter , Chang-Claude Jenny
Published: September 2011

Purpose

Lignans—plant-derived compounds with estrogen-dependent and -independent anticarcinogenic properties—have been associated with postmenopausal breast cancer risk, but data are limited regarding their effect on survival. Dietary lignans are metabolized to enterolignans, which are subsequently absorbed and become bioavailable.

Patients and Methods

We assessed the prognosis of 1,140 postmenopausal patients with breast cancer age 50 to 74 years who were diagnosed between 2002 and 2005. Vital status through the end of 2009 was ascertained via local population registries, and deaths were verified by death certificates. Information on recurrences and secondary tumors was verified by clinical records and attending physicians. Associations of postdiagnostic serum enterolactone (a biomarker for dietary lignans) with overall survival and distant disease-free survival were assessed by using Cox proportional hazards models stratified by age at diagnosis and adjusted for prognostic factors.

Results

Median enterolactone levels for deceased patients and those still alive were 17.0 and 21.4 nmol/L, respectively. During a median of 6.1 years of follow-up after diagnosis, 162 deaths were confirmed. Higher serum enterolactone levels were associated with significantly reduced hazard ratios (HRs) for death (HR per 10 nmol/L increment, 0.94; P = .04; HR for the highest quartile, 0.58; 95% CI, 0.34 to 0.99). For distant disease, HR was 0.94 per 10 nmol/L increment (P = .08) and 0.62 (95% CI, 0.35 to 1.09) for the highest quartile. The highest quartile of serum enterolactone was associated with a significantly reduced risk of death only for estrogen receptor–negative tumors (HR, 0.27; 95% CI, 0.08 to 0.87) but not for estrogen receptor–positive tumors (HR, 0.91; 95% CI, 0.45 to 1.84: P for heterogeneity = .09).

Conclusion

Postmenopausal patients with breast cancer who have high serum enterolactone levels may have better survival.
Soft-Tissue Plasmacytomas in Multiple Myeloma: Incidence, Mechanisms of Extramedullary Spread, and Treatment Approach
Authors: Bladé Joan , Fernández de Larrea Carlos , Rosiñol Laura , Cibeira María Teresa , Jiménez Raquel , Powles Ray
Published: September 2011

We provide an overview on soft-tissue extramedullary plasmacytomas (EMPs) in multiple myeloma (MM). We reviewed the incidence of EMPs in MM, myeloma bone marrow homing, possible mechanisms of extramedullary spread, and prognosis and response to therapy. The incidence of EMPs is 7% to 18% at MM diagnosis and up to 20% at relapse. The current notion that EMPs are more frequent after treatment with novel agents remains to be proven, especially considering that different patterns of disease recurrence can emerge as patients live longer in the era of novel drugs. Bone marrow genetic abnormalities are not associated with extramedullary spread per se, which also suggests that microenvironmental interactions are key. Possible mechanisms of extramedullary spread include decreased adhesion molecule expression and downregulation of chemokine receptors. EMPs usually show plasmablastic morphology with negative CD56 expression. High-dose therapy with autologous stem-cell transplantation (ASCT) can overcome the negative prognostic impact of extramedullary disease in younger selected patients. EMPs do not typically respond to thalidomide alone, but in contrast, responses to bortezomib have been reported. The incidence of EMPs in patients with MM is high and is associated with poor outcome in patients treated conventionally. A potential first-line treatment option seems to be a bortezomib-containing regimen followed by ASCT, whenever possible. Experimental studies on the mechanisms of myeloma cell adhesion, myeloma growth at extramedullary sites, and drug sensitivity are priorities for this area of continuing therapeutic challenge.
Response to Neoadjuvant Systemic Therapy for Breast Cancer in BRCA Mutation Carriers and Noncarriers: A Single-Institution Experience
Authors: Arun Banu , Bayraktar Soley , Liu Diane D. , Gutierrez Barrera Angelica M. , Atchley Deann , Pusztai Lajos , Litton Jennifer Keating , Valero Vicente , Meric-Bernstam Funda , Hortobagyi Gabriel N. , Albarracin Constance
Published: September 2011

Purpose

To compare the pathologic complete response (pCR) rate and relapse-free survival (RFS) and overall survival (OS) after neoadjuvant systemic chemotherapy (NST) in patients with breast cancer with and without deleterious BRCA1 and BRCA2 mutations.

Patients and Methods

A total of 317 women who underwent BRCA genetic testing and were treated with NST for breast cancer between 1997 and 2009 were included in the study. The Kaplan-Meier product-limit method was used to estimate RFS and OS rates. Logistic regression models were fit to determine the associations between BRCA status, pCR, and survival.

Results

Fifty-seven (18%) and 23 (7%) patients had BRCA1 and BRCA2 mutations, respectively. Twenty-six (46%) of 57 BRCA1 carriers achieved a pCR, compared with three (13%) of 23 BRCA2 carriers and 53 (22%) of 237 BRCA noncarriers (P < .001). In the multivariate logistic model, BRCA1 status (odds ratio [OR] = 3.16; 95% CI, 1.55 to 6.42; P = .002), estrogen receptor (ER) negativity (OR = 1.96; 95% CI:1.05 to 3.65; P = .03) and concurrent trastuzumab use (OR = 4.18; 95% CI, 2.04 to 8.57; P < .001) remained as independent significant predictors for a pCR. At a median follow-up of 3.2 years, 69 patients (22%) experienced a disease recurrence or death. No significant differences were noted in survival outcomes with respect to BRCA status and type of NST received. However, among BRCA1 carriers, patients who achieved a pCR had better 5-year RFS (P = .001) and OS (P = .01) rates than patients who did not.

Conclusion

BRCA1 status and ER negativity are independently associated with higher pCR rates in patients with breast cancer. Overall prognosis of breast cancer in BRCA carriers is similar to sporadic breast cancers.
Prevention of the Onset of Ovarian Hyperstimulation Syndrome (OHSS) in the Rat After Ovulation Induction with a Low Molecular Weight Agonist of the LH Receptor Compared with hCG and rec-LH
Authors: van de Lagemaat Ruud , Raafs B. C. , van Koppen C. , Timmers C. M. , Mulders S. M. , Hanssen R. G. J. M.
Published: September 2011

Ovarian hyperstimulation syndrome (OHSS) incidentally occurs in controlled ovarian stimulation protocols and is associated with human chorionic gonadotropin (hCG) administration. OHSS is caused by increased vascular permeability (VP) and thought to be mediated by hypersecretion of vascular endothelial growth factor (VEGF) by granulosa cells. Low molecular weight (LMW)-LH agonists have a similar mode of action but a shorter half-life compared with hCG, which could potentially lead to a clinical benefit in reducing the risk for OHSS in controlled ovarian stimulation protocols. The objective of this study is to investigate the role of an orally active LMW-LH agonist in OHSS induction compared with recombinant LH (rec-LH) and hCG. Immature rats were hyperstimulated with pregnant mare serum gonadotropin, and ovulation was induced by hCG, rec-LH or a LMW-LH agonist. The degree of VP was determined by Evans Blue in the abdominal cavity. Ovaries were weighed, and VEGF concentration in the ovary was determined. Pregnant mare serum gonadotropin stimulation followed by single-dose hCG or rec-LH resulted in clear enlargement of the ovaries and increased VP and VEGF levels. However, ovulation induction with a single dose of the LMW-LH agonist did not result in increased VP and VEGF levels, and even multiple dosing to mimic a longer exposure did not induce OHSS symptoms. In conclusion, we demonstrated that the oral LMW-LH agonist did not induce VP in rat, indicative for OHSS, possibly due to reduced VEGF production. If this is translatable to human, this could potentially represent a clinical benefit in reducing the risk for OHSS when using these compounds in controlled ovarian stimulation protocols.
Colocalization of FM1-43, Bassoon, and GnRH-1: GnRH-1 Release from Cell Bodies and Their Neuroprocesses
Authors: Fuenzalida Lidia C. , Keen Kim L. , Terasawa Ei
Published: September 2011

Pulsatile release of GnRH-1 is critical for reproductive function. However, the cellular mechanism of GnRH-1 neurosecretion is still elusive. In this study, we examined the neurosecretory process of GnRH-1 neurons using time-lapse image acquisition followed by immunocytochemistry with confocal microscopy. To monitor exocytotic processes, cultured GnRH-1 neurons derived from monkey embryos were labeled with the lipophilic dye, FM1-43, or its fixable form FM1-43Fx, in the presence or absence of depolarization signals, and changes in vesicles labeled with FM1-43 were analyzed. The results show FM1-43 was taken up into the cell and labeled puncta in the soma and neuroprocesses in the absence of depolarization signals, indicating that GnRH-1 neurons were spontaneously active. Depolarization of GnRH-1 neurons with high K+ or veratridine challenge increased the intensity and size of puncta in both soma and neuroprocesses, and the veratridine-induced changes in puncta were blocked by tetrodotoxin, indicating that changes in the puncta intensity and size reflect neurosecretory activity. Subsequent double immunocytochemistry for GnRH-1 and the synaptic vesicle marker, vesicle-associated membrane protein, demonstrated that the FM1-43Fx-labeled puncta were synaptic vesicles with the GnRH-1 peptide. Additional double immunocytochemistry for GnRH-1 and the marker of the neurosecretory active zone, Bassoon, indicated that the FM1-43Fx-labeled puncta were located at the sites of neurosecretory active zones in GnRH-1 neurons. These results suggest that GnRH-1 neurons have the capacity to release the peptide from the soma and dendrites. Collectively, we hypothesize that soma-dendritic release of the peptide may be a mechanism of synchronized activity among GnRH-1 neurons.
The novel transmembrane protein Tmem2 is essential for coordination of myocardial and endocardial morphogenesis
Authors: Totong Ronald , Schell Thomas , Lescroart Fabienne , Ryckebüsch Lucile , Lin Yi-Fan , Zygmunt Tomasz , Herwig Lukas , Krudewig Alice , Gershoony Dafna , Belting Heinz-Georg , Affolter Markus , Torres-Vázquez Jesús , Yelon Deborah
Published: September 2011

Coordination between adjacent tissues plays a crucial role during the morphogenesis of developing organs. In the embryonic heart, two tissues – the myocardium and the endocardium – are closely juxtaposed throughout their development. Myocardial and endocardial cells originate in neighboring regions of the lateral mesoderm, migrate medially in a synchronized fashion, collaborate to create concentric layers of the heart tube, and communicate during formation of the atrioventricular canal. Here, we identify a novel transmembrane protein, Tmem2, that has important functions during both myocardial and endocardial morphogenesis. We find that the zebrafish mutation frozen ventricle (frv) causes ectopic atrioventricular canal characteristics in the ventricular myocardium and endocardium, indicating a role of frv in the regional restriction of atrioventricular canal differentiation. Furthermore, in maternal-zygotic frv mutants, both myocardial and endocardial cells fail to move to the midline normally, indicating that frv facilitates cardiac fusion. Positional cloning reveals that the frv locus encodes Tmem2, a predicted type II single-pass transmembrane protein. Homologs of Tmem2 are present in all examined vertebrate genomes, but nothing is known about its molecular or cellular function in any context. By employing transgenes to drive tissue-specific expression of tmem2, we find that Tmem2 can function in the endocardium to repress atrioventricular differentiation within the ventricle. Additionally, Tmem2 can function in the myocardium to promote the medial movement of both myocardial and endocardial cells. Together, our data reveal that Tmem2 is an essential mediator of myocardium-endocardium coordination during cardiac morphogenesis.
HP1γ links histone methylation marks to meiotic synapsis in mice
Authors: Takada Yuki , Naruse Chie , Costa Yael , Shirakawa Takayuki , Tachibana Makoto , Sharif Jafar , Kezuka-Shiotani Fuyuko , Kakiuchi Dai , Masumoto Hiroshi , Shinkai Yo-ichi , Ohbo Kazuyuki , Peters Antoine H. F. M. , Turner James M. A. , Asano Masahide , Koseki Haruhiko
Published: September 2011

During meiosis, specific histone modifications at pericentric heterochromatin (PCH), especially histone H3 tri- and dimethylation at lysine 9 (H3K9me3 and H3K9me2, respectively), are required for proper chromosome interactions. However, the molecular mechanism by which H3K9 methylation mediates the synapsis is not yet understood. We have generated a Cbx3-deficient mouse line and performed comparative analysis on Suv39h1/h2-, G9a- and Cbx3-deficient spermatocytes. This study revealed that H3K9me2 at PCH depended on Suv39h1/h2-mediated H3K9me3 and its recognition by the Cbx3 gene product HP1γ. We further found that centromere clustering and synapsis were commonly affected in G9a- and Cbx3-deficient spermatocytes. These genetic observations suggest that HP1γ/G9a-dependent PCH-mediated centromere clustering is an axis for proper chromosome interactions during meiotic prophase. We propose that the role of the HP1γ/G9a axis is to retain centromeric regions of unpaired homologous chromosomes in close alignment and facilitate progression of their pairing in early meiotic prophase. This study also reveals considerable plasticity in the interplay between different histone modifications and suggests that such stepwise and dynamic epigenetic modifications may play a pivotal role in meiosis.
Modeling new conceptual interpretations of development
Authors: Vermot Julien , Affolter Markus
Published: September 2011

In April 2011, researchers from diverse background met at the Gulbenkian Institute (Oeiras, Portugal) to discuss the emerging input of biophysics into the field of developmental biology. The scope of the workshop was to bring together scientists working in different model systems and to discuss some of the most recent advances towards understanding how physical forces affect embryonic development. Discussions and talks highlighted two main trends: that many aspects of embryogenesis can be accurately quantified and translated into a limited number of physical forces and biochemical parameters; and that simulations and modeling provide new conceptual interpretations of classical developmental questions.
Specific expression of a TRIM-containing factor in ectoderm cells affects the skeletal morphogenetic program of the sea urchin embryo
Authors: Cavalieri Vincenzo , Guarcello Rosa , Spinelli Giovanni
Published: September 2011

In the indirect developing sea urchin embryo, the primary mesenchyme cells (PMCs) acquire most of the positional and temporal information from the overlying ectoderm for skeletal initiation and growth. In this study, we characterize the function of the novel gene strim1, which encodes a tripartite motif-containing (TRIM) protein, that adds to the list of genes constituting the epithelial-mesenchymal signaling network. We report that strim1 is expressed in ectoderm regions adjacent to the bilateral clusters of PMCs and that its misexpression leads to severe skeletal abnormalities. Reciprocally, knock down of strim1 function abrogates PMC positioning and blocks skeletogenesis. Blastomere transplantation experiments establish that the defects in PMC patterning, number and skeletal growth depend upon strim1 misexpression in ectoderm cells. Furthermore, clonal expression of strim1 into knocked down embryos locally restores skeletogenesis. We also provide evidence that the Otp and Pax2/5/8 regulators, as well as FGFA, but not VEGF, ligand act downstream to strim1 in ectoderm cells, and that strim1 triggers the expression of the PMC marker sm30, an ectoderm-signaling dependent gene. We conclude that the strim1 function elicits specific gene expression both in ectoderm cells and PMCs to guide the skeletal biomineralization during morphogenesis.
Very-long-chain fatty acids are required for cell plate formation during cytokinesis inArabidopsis thaliana
Authors: Bach Liên , Gissot Lionel , Marion Jessica , Tellier Frédérique , Moreau Patrick , Satiat-Jeunemaître Béatrice , Palauqui Jean-Christophe , Napier Johnathan A. , Faure Jean-Denis
Published: September 2011

Acyl chain length is thought to be crucial for biophysical properties of the membrane, in particular during cell division, when active vesicular fusion is necessary. In higher plants, the process of cytokinesis is unique, because the separation of the two daughter cells is carried out by de novo vesicular fusion to generate a laterally expanding cell plate. In Arabidopsis thaliana, very-long-chain fatty acid (VLCFA) depletion caused by a mutation in the microsomal elongase gene PASTICCINO2 (PAS2) or by application of the selective elongase inhibitor flufenacet altered cytokinesis. Cell plate expansion was delayed and the formation of the endomembrane tubular network altered. These defects were associated with specific aggregation of the cell plate markers YFP–Rab-A2a and KNOLLE during cytokinesis. Changes in levels of VLCFA also resulted in modification of endocytosis and sensitivity to brefeldin A. Finally, the cytokinesis impairment in pas2 cells was associated with reduced levels of very long fatty acyl chains in phospholipids. Together, our findings demonstrate that VLCFA-containing lipids are essential for endomembrane dynamics during cytokinesis.
DrosophilaSwiprosin-1/EFHD2 accumulates at the prefusion complex stage duringDrosophilamyoblast fusion
Authors: Hornbruch-Freitag Christina , Griemert Barbara , Buttgereit Detlev , Renkawitz-Pohl Renate
Published: September 2011

In the Drosophila embryo, transient cell adhesion during myoblast fusion is known to lead to the formation of fusion-restricted myogenic-adhesive structures (FuRMASs). Here, we report that within these FuRMASs, a Drosophila homologue of human and mouse swiprosins (EF-hand-domain-containing proteins) is expressed, which we named Drosophila Swiprosin-1 (Drosophila Swip-1). Drosophila Swip-1 is highly conserved and is closely related to the calcium-binding proteins swiprosin-1 and swiprosin-2 that have a role in the immune system in humans and mice. Our study shows that Drosophila Swip-1 is also expressed in corresponding cells of the Drosophila immune system. During myoblast fusion, Drosophila Swip-1 accumulates transiently in the foci of fusion-competent myoblasts (FCMs). Both the EF-hand and the coiled-coil domain of Drosophila Swip-1 are required to localise the protein to these foci. The formation of Drosophila Swip-1 foci requires successful cell adhesion between FCMs and founder cells (FCs) or growing myotubes. Moreover, Drosophila Swip-1 foci were found to increase in number in sing22 mutants, which arrest myoblast fusion after prefusion complex formation. By contrast, Drosophila Swip-1 foci are not significantly enriched in blow2 and ketteJ4-48 mutants, which stop myogenesis beyond the prefusion complex stage but before plasma membrane merging. Therefore, we hypothesise that Drosophila Swip-1 participates in the breakdown of the prefusion complex during the progression of myoblast fusion.