bluuebunny/crossref_metadata_2025_split huggingface dataset:
Maternal pre-pregnancy weight and externalising behaviour problems in preschool children: a UK-based twin study
Authors: Antoniou Evangelia E , Fowler Tom , Reed Keith , Southwood Taunton R , McCleery Joseph P , Zeegers Maurice P 
Published: October 2014

ObjectiveTo estimate the heritability of child behaviour problems and investigate the association between maternal pre-pregnancy overweight and child behaviour problems in a genetically sensitive design.DesignObservational cross-sectional study.SettingThe Twins and Multiple Births Association Heritability Study (TAMBAHS) is an online UK-wide volunteer-based study investigating the development of twins from birth until 5 years of age.ParticipantsA total of 443 (16% of the initial registered members) mothers answered questions on pre-pregnancy weight and their twins’ internalising and externalising problems using the Child Behavior Checklist and correcting for important covariates including gestational age, twins’ birth weight, age and sex, mother's educational level and smoking (before, during and after pregnancy).Primary outcomesThe heritability of behaviour problems and their association with maternal pre-pregnancy weight.ResultsThe genetic analysis suggested that genetic and common environmental factors account for most of the variation in externalising disorders (an ACE model was the most parsimonious with genetic factors (A) explaining 46% (95% CI 33% to 60%) of the variance, common environment (C) explaining 42% (95% CI 27% to 54%) and non-shared environmental factors (E) explaining 13% (95% CI 10% to 16%) of the variance. For internalising problems, a CE model was the most parsimonious model with the common environment explaining 51% (95% CI 44% to 58%) of the variance and non-shared environment explaining 49% (95% CI 42% to 56%) of the variance. Moreover, the regression analysis results suggested that children of overweight mothers showed a trend (OR=1.10, 95% CI 0.58% to 2.06) towards being more aggressive and exhibit externalising behaviours compared to children of normal weight mothers.ConclusionsMaternal pre-pregnancy weight may play a role in children's aggressive behaviour.
Overdetection of Recurrence after Radical Prostatectomy: Estimates Based on Patient and Tumor Characteristics
Authors: Xia Jing , Trock Bruce J. , Gulati Roman , Mallinger Leslie , Cooperberg Matthew R. , Carroll Peter R. , Carter H. Ballentine , Etzioni Ruth 
Published: October 2014

Abstract
Purpose: Prostate-specific antigen recurrence (PSA-R) after radical prostatectomy (RP) can occur years before metastasis. This study estimates the chance that an untreated PSA-R would not progress to clinical metastasis within the patient's lifetime, that is, that recurrence is overdetected.
Experimental Design: Times from PSA-R to metastasis were estimated from patients with RP treated at Johns Hopkins University (Baltimore, MD) who did not receive salvage treatment (n = 441) at PSA-R. Times to other-cause death were based on U.S. life tables adjusted to reflect other-cause survival among RP cases in the Surveillance, Epidemiology, and End Results (SEER) registry. We used competing risks simulation to estimate lower bounds on the chance that other-cause death would precede clinical metastasis for patients with disease characteristics at diagnosis based on the Cancer of the Prostate Strategic Urologic Research Endeavor (CaPSURE) database (n = 4,455).
Results: Cumulative incidence of PSA-R in CaPSURE was 13.6% at 5 years and 19.9% at 10 years. The risk of other-cause death among patients with RP in SEER was 60% lower than the age-matched U.S. population. At least 9.1% of patients with PSA-R &lt;5 years after RP and at least 15.6% of patients with PSA-R 5 to 10 years after RP were overdetected. At least 31.4% of patients over the age of 70 years at diagnosis, who recurred &lt;10 years of diagnosis, were overdetected.
Conclusions: This analysis indicates that PSA-R after RP may be overdetected, with risk depending on patient age and tumor characteristics. The potential for overdetection of recurrence confirms the need for approaches to determine whether and when to initiate salvage therapies. Clin Cancer Res; 20(20); 5302–10. ©2014 AACR.
Precision Treatment of Distinct Molecular Subtypes of Diffuse Large B-cell Lymphoma: Ascribing Treatment Based on the Molecular Phenotype
Authors: Dunleavy Kieron , Roschewski Mark , Wilson Wyndham H. 
Published: October 2014

Abstract
Although diffuse large B-cell lymphoma (DLBCL), the most common type of non-Hodgkin lymphoma, was once considered to be a single disease, novel insights into its biology have revealed that it is molecularly heterogeneous. Technologies such as gene expression profiling have revealed that DLBCL consists of at least three distinct molecular diseases that have disparate outcomes following standard therapy. These subtypes arise from different stages of B-cell differentiation and are characterized by distinct oncogenic activation mechanisms. This knowledge has led to the investigation of strategies and novel agents that have selective activity within molecular subtypes and sets the stage for an era of precision medicine in DLBCL therapeutics, where therapy can be ascribed based on molecular phenotype. This work offers the chance of improving the curability of DLBCL, particularly in the activated B-cell subtype, where standard approaches are inadequate for a high proportion of patients.
See all articles in this CCR Focus section, “Paradigm Shifts in Lymphoma.”
Clin Cancer Res; 20(20); 5182–93. ©2014 AACR.
Human T-cell Lymphotropic Virus Type I–Associated Adult T-cell Leukemia–Lymphoma: New Directions in Clinical Research
Authors: Tsukasaki Kunihiro , Tobinai Kensei 
Published: October 2014

Abstract
Adult T-cell leukemia–lymphoma (ATL) is a distinct malignancy of regulatory T cell (Treg)/TH2 cells caused by human T-cell lymphotropic virus type I (HTLV-1), with a high frequency of expression of CD3/CD4/CD25/CCR4 and FoxP3 in about half of the cells. However, in primary ATL cells, although expression of the virus, including the Tax oncoprotein, appears just after an in vitro culture, integration sites of the provirus into the host genome are random, and chromosomal/genetic abnormalities are complex. ATL is thus a single disease entity that is caused by HTLV-1 and possesses diverse molecular features. The clinical features and prognosis of ATL vary, and this has led to subtypes classified into four categories: acute, lymphomatous, chronic, and smoldering types, based on lactate dehydrogenase and calcium values and organ involvement. Approximately 15 to 20 million individuals are infected with HTLV-1 worldwide, 1.1 million of whom reside in Japan, and the annual incidence of ATL has been estimated to be approximately 1,000. HTLV-1 infection early in life, mainly from breast feeding, is crucial for the development of ATL. The age-specific occurrence of ATL and complex genome abnormalities that accumulate with disease progression suggest a multistep carcinogenesis model following HTLV-1 infection. Various treatment options are available for ATL and consist of watchful waiting for indolent ATL, intensive chemotherapy followed by allogeneic hematopoietic stem cell transplantation for aggressive ATL, and a combination of IFNα and zidovudine for ATL with leukemic manifestation. Several promising new agents, including an anti-CCR4 antibody, are currently undergoing clinical trials associated with translational research.
See all articles in this CCR Focus section, “Paradigm Shifts in Lymphoma.”
Clin Cancer Res; 20(20); 5217–25. ©2014 AACR.
Genomic Classification of Serous Ovarian Cancer with Adjacent Borderline Differentiates RAS Pathway and TP53-Mutant Tumors and Identifies NRAS as an Oncogenic Driver
Authors: Emmanuel Catherine , Chiew Yoke-Eng , George Joshy , Etemadmoghadam Dariush , Anglesio Michael S. , Sharma Raghwa , Russell Peter , Kennedy Catherine , Fereday Sian , Hung Jillian , Galletta Laura , Hogg Russell , Wain Gerard V. , Brand Alison , Balleine Rosemary , MacConaill Laura , Palescandolo Emanuele , Hunter Sally M. , Campbell Ian , Dobrovic Alexander , Wong Stephen Q. , Do Hongdo , Clarke Christine L. , Harnett Paul R. , Bowtell David D.L. , deFazio Anna 
Published: October 2014

Abstract
Purpose: Low-grade serous ovarian carcinomas (LGSC) are Ras pathway-mutated, TP53 wild-type, and frequently associated with borderline tumors. Patients with LGSCs respond poorly to platinum-based chemotherapy and may benefit from pathway-targeted agents. High-grade serous carcinomas (HGSC) are TP53-mutated and are thought to be rarely associated with borderline tumors. We sought to determine whether borderline histology associated with grade 2 or 3 carcinoma was an indicator of Ras mutation, and we explored the molecular relationship between coexisting invasive and borderline histologies.
Experimental Design: We reviewed &gt;1,200 patients and identified 102 serous carcinomas with adjacent borderline regions for analyses, including candidate mutation screening, copy number, and gene expression profiling.
Results: We found a similar frequency of low, moderate, and high-grade carcinomas with coexisting borderline histology. BRAF/KRAS alterations were common in LGSC; however, we also found recurrent NRAS mutations. Whereas borderline tumors harbored BRAF/KRAS mutations, NRAS mutations were restricted to carcinomas, representing the first example of a Ras oncogene with an obligatory association with invasive serous cancer. Coexisting borderline and invasive components showed nearly identical genomic profiles. Grade 2 cases with coexisting borderline included tumors with molecular features of LGSC, whereas others were typical of HGSC. However, all grade 3 carcinomas with coexisting borderline histology were molecularly indistinguishable from typical HGSC.
Conclusion: Our findings suggest that NRAS is an oncogenic driver in serous ovarian tumors. We demonstrate that borderline histology is an unreliable predictor of Ras pathway aberration and underscore an important role for molecular classification in identifying patients that may benefit from targeted agents. Clin Cancer Res; 20(24); 6618–30. ©2014 AACR.
New Strategies in Ovarian Cancer: Translating the Molecular Complexity of Ovarian Cancer into Treatment Advances
Authors: Liu Joyce , Matulonis Ursula A. 
Published: October 2014

Abstract
An improved understanding of the genomics of ovarian cancer and the separation of ovarian cancer into histologically and molecularly defined subgroups have affected drug development and clinical trial design in ovarian cancer. Active therapies that have been tested in ovarian cancer include agents that inhibit angiogenesis and poly (ADP-ribose) polymerase inhibitors (PARPi). However, no FDA drug approvals for ovarian cancer have been granted since 2006, and overall survival improvements have been difficult to achieve with new agents. The genomic complexity of ovarian cancer and modest single-agent activity of many biologic agents in this disease have led to testing of biologic agent combinations. In this article, we review recent advances in the understanding of the molecular diversity of ovarian cancer as well as emerging therapeutic strategies such as new agents and biologic combinations that attempt to target multiple aberrant pathways in this cancer. Clin Cancer Res; 20(20); 5150–6. ©2014 AACR.
The Novel, Small-Molecule DNA Methylation Inhibitor SGI-110 as an Ovarian Cancer Chemosensitizer
Authors: Fang Fang , Munck Joanne , Tang Jessica , Taverna Pietro , Wang Yinu , Miller David F.B. , Pilrose Jay , Choy Gavin , Azab Mohammad , Pawelczak Katherine S. , VanderVere-Carozza Pamela , Wagner Michael , Lyons John , Matei Daniela , Turchi John J. , Nephew Kenneth P. 
Published: October 2014

Abstract
Purpose: To investigate SGI-110 as a “chemosensitizer” in ovarian cancer and to assess its effects on tumor suppressor genes (TSG) and chemoresponsiveness-associated genes silenced by DNA methylation in ovarian cancer.
Experimental Design: Several ovarian cancer cell lines were used for in vitro and in vivo platinum resensitization studies. Changes in DNA methylation and expression levels of TSG and other cancer-related genes in response to SGI-110 were measured by pyrosequencing and RT-PCR.
Results: We demonstrate in vitro that SGI-110 resensitized a range of platinum-resistant ovarian cancer cells to cisplatin (CDDP) and induced significant demethylation and reexpression of TSG, differentiation-associated genes, and putative drivers of ovarian cancer cisplatin resistance. In vivo, SGI-110 alone or in combination with CDDP was well tolerated and induced antitumor effects in ovarian cancer xenografts. Pyrosequencing analyses confirmed that SGI-110 caused both global (LINE1) and gene-specific hypomethylation in vivo, including TSGs (RASSF1A), proposed drivers of ovarian cancer cisplatin resistance (MLH1 and ZIC1), differentiation-associated genes (HOXA10 and HOXA11), and transcription factors (STAT5B). Furthermore, DNA damage induced by CDDP in ovarian cancer cells was increased by SGI-110, as measured by inductively coupled plasma-mass spectrometry analysis of DNA adduct formation and repair of cisplatin-induced DNA damage.
Conclusions: These results strongly support further investigation of hypomethylating strategies in platinum-resistant ovarian cancer. Specifically, SGI-110 in combination with conventional and/or targeted therapeutics warrants further development in this setting. Clin Cancer Res; 20(24); 6504–16. ©2014 AACR.
Rac1 Signaling Is Critical to Cardiomyocyte Polarity and Embryonic Heart Development
Authors: Leung Carmen , Lu Xiangru , Liu Murong , Feng Qingping 
Published: October 2014

Background

Defects in cardiac septation are the most common form of congenital heart disease, but the mechanisms underlying these defects are still poorly understood. The small
GTP
ase Rac1 is implicated in planar cell polarity of epithelial cells in
Drosophila
; however, its role in mammalian cardiomyocyte polarity is not clear. We tested the hypothesis that Rac1 signaling in the second heart field regulates cardiomyocyte polarity, chamber septation, and right ventricle development during embryonic heart development.

Methods and Results

Mice with second heart field–specific deficiency of
Rac1
(
Rac1

SHF

) exhibited ventricular and atrial septal defects, a thinner right ventricle myocardium, and a bifid cardiac apex. Fate‐mapping analysis showed that second heart field contribution to the interventricular septum and right ventricle was deficient in
Rac1

SHF

hearts. Notably, cardiomyocytes had a spherical shape with disrupted F‐actin filaments in
Rac1

SHF

compared with elongated and well‐aligned cardiomyocytes in littermate controls. Expression of Scrib, a core protein in planar cell polarity, was lost in
Rac1

SHF

hearts with decreased expression of

WAVE

and
Arp2/3
, leading to decreased migratory ability. In addition, Rac1‐deficient neonatal cardiomyocytes displayed defects in cell projections, lamellipodia formation, and cell elongation. Furthermore, apoptosis was increased and the expression of
Gata4
,
Tbx5
,
Nkx2.5
, and
Hand2
transcription factors was decreased in the
Rac1

SHF

right ventricle myocardium.

Conclusions
Deficiency of Rac1 in the second heart field impairs elongation and cytoskeleton organization of cardiomyocytes and results in congenital septal defects, thin right ventricle myocardium, and a bifid cardiac apex. Our study suggests that Rac1 signaling is critical to cardiomyocyte polarity and embryonic heart development.
Use of Coumarin Anticoagulants and Cerebral Microbleeds in the General Population
Authors: Akoudad Saloua , Darweesh Sirwan K.L. , Leening Maarten J.G. , Koudstaal Peter J. , Hofman Albert , van der Lugt Aad , Stricker Bruno H. , Ikram M. Arfan , Vernooij Meike W. 
Published: October 2014

Background and Purpose—
It remains undetermined whether the use of coumarin anticoagulants associates with cerebral microbleeds in the general population. We investigated whether (1) coumarin use relates to higher prevalence and incidence of microbleeds, (2) microbleeds are more frequent in people with higher maximum international normalized ratios (INRs), and (3) among coumarin users, variability in INR associates with microbleed presence.

Methods—
From the population-based Rotterdam Study, 4945 participants aged ≥45 years were included in the cross-sectional analysis, and 3069 participants had follow-up brain MRI. Information on coumarin use was obtained from automated pharmacy records. Coumarin users were monitored, and INR values were measured in consecutive visits. Presence and location of microbleeds were rated on brain MRI. We investigated the association of coumarin use with microbleeds using multivariable logistic regression.

Results—
Overall, 8.6% had used coumarin anticoagulants before the first MRI and 5.9% before follow-up MRI. The prevalence of microbleeds was 19.4%, and the incidence was 6.9% during a mean follow-up of 3.9 years (SD, 0.5). Compared with never users, coumarin users had a higher prevalence of deep or infratentorial microbleeds and a higher incidence of any microbleeds, although statistical significance was not reached in the latter. A higher maximum INR was associated with deep or infratentorial microbleeds. Among coumarin users, a greater variability in INR was associated with a higher prevalence of microbleeds.

Conclusions—
Coumarin use is associated with microbleeds. Associations were strongest for people with greater variability in INR.
Group size, contest competition, and social structure in Cayo Santiago rhesus macaques
Authors: Balasubramaniam K.N. , Dunayer E.S. , Gilhooly L.J. , Rosenfield K.A. , Berman C.M. 
Published: October 2014

In non-human primate systems, the Ecological Model of Female Social Relationships (EMFSR) views variation in female social structure as adaptations to variation in recent past and/or current ecological conditions. Group size may be a major additional demographic factor affecting social structure through its effects on resource competition. In particular, in Resident Nepotistic Despotic (RND) societies, when resources are uniformly clumped, larger groups are expected to face higher levels of within-group contest competition (WGC) than smaller groups and to respond by showing more highly despotic social relationships than smaller groups. On the other hand, smaller groups are expected to face higher levels of between-group contest competition (BGC) and hence, show greater levels of intragroup tolerance (or lower despotism). While formal models do not explicitly predict this kind of variation within species, many researchers have investigated such intraspecific variation. Thus, we tested these predictions across three groups of free-ranging rhesus macaques (Macaca mulatta) of varying sizes on Cayo Santiago, Puerto Rico, where we were able to control for variation in resource-patch contestability and predation risk. Subjects were adult females. For each group, we collected data on (1) exposure and (2) behavioural reactions to WGC and BGC at two independent sets of clumped resources (feeding corrals and drinking stations) and (3) agonistic and affiliative social behaviour, using focal animal, all occurrences, and ad-libitum sampling methods. As predicted, our largest group showed the greatest levels of exposure and behavioural responses to WGC contexts. Likewise, our smallest group showed greatest levels of exposure and responses to BGC contexts. However, aspects of social structure did not vary across groups in directions predicted by the EMFSR. These findings are broadly consistent with several previous comparative tests of the model on other primate taxa that found strong links between group size, ecological factors and contest competitive regimes, but little or no evidence of links with social structure. Our study adds strength to these conclusions given our unique ability to control for several variables on Cayo Santiago. We suggest that our findings may be generalizable to several wild rhesus populations in North India, given that they have lived in similarly dense populations and have been frequently provisioned by humans for thousands of years.
An experimental study measuring the effects of a tarsus-mounted tracking device on the behaviour of a small pursuit-diving seabird
Authors: Robinson Jill L. , Jones Ian Lawrence 
Published: October 2014

Miniaturized tracking devices are taking a rapidly increasing role in studies measuring animal movement and other aspects of behaviour, especially for wide-ranging species such as seabirds that are difficult to observe otherwise. A crucial, but questionable criterion of such migration research is assuming that effects of tracking devices on animal behaviour are negligible, to ensure results of tracking studies are biologically relevant. To address this concern, we experimentally quantified effects of a 2 g (ca. 1.1% of body mass) geolocation device on crested auklet (Aethia cristatella) behaviour, including return rate, activity on the colony surface, and measures of reproductive performance in a two-year, two-part field study. In experiment 1, we fitted tracking devices (or identical dummy devices) to one mate of a breeding pair in nesting crevices, to quantify effects on reproductive performance and nest fidelity. In experiment 2, we assigned dummy devices to birds captured at the colony site surface, to quantify effects on social activity, return rate and provisioning behaviour. For birds tagged in crevices, we detected no effect on fledging success, or chick growth rate (mass and wing length). However, mass at fledging age of chicks provisioned with one tagged parent was significantly lower than control, and low nest site fidelity (compared to control birds) was observed for tagged birds. Individuals tagged on the colony surface showed significantly reduced colony surface activity, return rates and provisioning behaviour. This study shows strong ‘observer effects’ of an attached device well below the recommended size limit for wildlife tagging. Future studies should both quantify effects of attached devices and consider the biological relevance of measures of the behaviour of interest.
Numerical Evidence of Turbulence Generated by Nonbreaking Surface Waves
Authors: Tsai Wu-ting , Chen Shi-ming , Lu Guan-hung 
Published: October 2014

AbstractNumerical simulation of monochromatic surface waves propagating over a turbulent field is conducted to reveal the mechanism of turbulence production by nonbreaking waves. The numerical model solves the primitive equations subject to the fully nonlinear boundary conditions on the exact water surface. The result predicts growth rates of turbulent kinetic energy consistent with previous measurements and modeling. It also validates the observed horizontal anisotropy of the near-surface turbulence that the spanwise turbulent intensity exceeds the streamwise component. Such a flow structure is found to be attributed to the formation of streamwise vortices near the water surface, which also induces elongated surface streaks. The averaged spacing between the streaks and the depth of the vortical cells approximates that of Langmuir turbulence. The strength of the vortices arising from the wave–turbulence interaction, however, is one order of magnitude less than that of Langmuir cells, which arises from the interaction between the surface waves and the turbulent shear flow. In contrast to Langmuir turbulence, production from the Stokes shear does not dominate the energetics budget in wave-induced turbulence. The dominant production is the advection of turbulence by the velocity straining of waves.