bluuebunny/crossref_metadata_2025_split huggingface dataset:
Artificially selected human sperm morphology after swim-up processing
Authors: Vladić Tomislav , Petersson Erik 
Published: September 2012

The swim-up technique is a clinical practice used to select highly motile sperm cells from patient ejaculates to use in assisted fertilization. The aim of this study was to investigate whether the length of different sperm-cell components is related to gamete function. Thus, we explored whether swim-up technique selects for longer sperm cells than mean sperm cells from unprocessed ejaculates. Sperm midpiece, tail endpiece, and total length were measured before and after the swim-up selection by means of contrast-phase and electron microscopy. Correlations between sperm dimensions, sperm motility, and sperm concentration were also investigated. Swim-up selected cells with longer midpiece compared with the unprocessed fractions (5.8 μm (CI 5.52–6.16 μm) vs. 5.3 μm (CI 4.97–5.61 μm), p < 0.05) and shorter tail endpiece (7.8 μm (CI 7.11–8.44 μm) vs. 8.5 μm (CI 7.81–9.14 μm), p < 0.05 after meta-analysis), whereas no effect of swim-up selection was detected on the total sperm cell length. Individuals producing high sperm concentrations had longer sperm midpiece than had men producing lower sperm concentrations. It is concluded that short sperm flagellar tips with long midpieces may be used as biomarkers in infertility therapy.
Female Eastern Hog-nosed Snakes (Heterodon platirhinos) choose nest sites that produce offspring with phenotypes likely to improve fitness
Authors: Peet-Paré C.A. , Blouin-Demers G. 
Published: September 2012

Nest-site selection is an important behaviour in oviparous reptiles because incubation conditions affect offspring phenotype, with favourable conditions leading to higher offspring fitness. We aimed to identify the habitat characteristics involved in nest-site selection in Eastern Hog-nosed Snakes ( Heterodon platirhinos Latreille, 1801) and to determine whether females select nest sites that result in offspring with phenotypes likely to improve fitness. We compared the habitat characteristics and temperature profiles of 21 nests with 21 randomly selected sites. Eastern Hog-nosed Snakes selected open, grassy sites with less herbs and shrubs than random sites, and nests were significantly warmer than random sites during the 2 years of the study. In the second year of the study, we incubated 215 eggs from eight nests in a split-clutch design at mean nest (24 °C) and random site (22 °C) temperatures approximating those of the first year of the study. Eggs incubated at 24 °C resulted in neonates that hatched earlier, had fewer scale anomalies, were larger, and swam faster than neonates from eggs incubated at 22 °C. Our results indicate that Eastern Hog-nosed Snakes select nest sites that lead to offspring with phenotypes likely to improve fitness.
Variation in catchment areas of Indiana bat (Myotis sodalis) hibernacula inferred from stable hydrogen (δ2H) isotope analysis
Authors: Britzke E.R. , Loeb S.C. , Romanek C.S. , Hobson K.A. , Vonhof M.J. 
Published: September 2012

Understanding seasonal movements of bats is important for effective conservation efforts. Although female Indiana bats ( Myotis sodalis Miller and Allen, 1928) have been documented to migrate >500 km, knowledge of their migratory patterns is still extremely limited. We used the relationship between latitude and stable hydrogen isotope ratio in bat hair (δ2Hhair) to estimate the north–south extent of the summer range (catchment area) of bats hibernating in 14 Indiana bat hibernacula in eight states throughout its range. Range of δ2Hhair values varied substantially among hibernacula, suggesting large differences among sites in the north–south distance travelled by bats between summer and winter habitats. In particular, hibernacula in the southern portion of the range had greater catchment areas than those in the central and northern portions of the range. Variability in movement distances among sites was not associated with the number of hair samples analyzed or colony size. Significant year-to-year variation (2007–2008 to 2008–2009) in the distribution of δ2Hhair for two sites in Tennessee was observed. Currently, hibernacula considered important for species conservation are largely determined by population size, but our results suggest that migratory diversity should also be considered.
Rock magnetic characterization of early and late diagenesis in a stratigraphic well from the Llanos foreland basin (Eastern Colombia)
Authors: Costanzo-Álvarez Vincenzo , Aldana Milagrosa , Bayona Germán , López-Rodríguez Diego , Blanco Joan Marie 
Published: September 2012

Abstract
We have carried out rock magnetic characterizations of different lithofacies along the stratigraphic well Saltarín 1A, in order to learn about the various diagenetic events that could have affected the Miocene sequence of the Llanos foreland basin (Colombia). Thermomagnetic and low-temperature susceptibility measurements performed on some selected samples were complemented with analyses of Scanning Electron Microscopy (SEM), Energy Dispersive X-ray (EDX) and isothermal remanent magnetization (IRM) acquisition curves. The identification of the magnetic mineral assemblages at each depth level analysed, as well as their relative concentrations, were determined from a direct signal analysis (DSA) of the IRM curves. Samples from the top of the Guayabo formation reveal the presence of hydrocarbons-related microscopic framboids of pyrite with partial replacement of magnetite. The bottom of the Guayabo formation shows hematite and goethite and appears to record a thoroughly documented Middle Miocene global regression. In samples from the León formation, pyrrhotite could have resulted from an early diagenesis that took place in a lacustrine environment via sulphate reduction. Traces of crude oil in samples from the Carbonera formation, and the additional occurrence of hematite and magnetite, suggest that a hydrocarbons-mediated late diagenesis could also have affected the lowermost levels of Saltarín 1A.
Halofuginone Inhibits the Establishment and Progression of Melanoma Bone Metastases
Authors: Juárez Patricia , Mohammad Khalid S. , Yin Juan Juan , Fournier Pierrick G. J. , McKenna Ryan C. , Davis Holly W. , Peng Xiang H. , Niewolna Maria , Javelaud Delphine , Chirgwin John M. , Mauviel Alain , Guise Theresa A. 
Published: September 2012

Abstract
TGF-β derived from bone fuels melanoma bone metastases by inducing tumor secretion of prometastatic factors that act on bone cells to change the skeletal microenvironment. Halofuginone is a plant alkaloid derivative that blocks TGF-β signaling with antiangiogenic and antiproliferative properties. Here, we show for the first time that halofuginone therapy decreases development and progression of bone metastasis caused by melanoma cells through the inhibition of TGF-β signaling. Halofuginone treatment of human melanoma cells inhibited cell proliferation, phosphorylation of SMAD proteins in response to TGF-β, and TGF-β–induced SMAD-driven transcription. In addition, halofuginone reduced expression of TGF-β target genes that enhance bone metastases, including PTHrP, CTGF, CXCR4, and IL11. Also, cell apoptosis was increased in response to halofuginone. In nude mice inoculated with 1205Lu melanoma cells, a preventive protocol with halofuginone inhibited bone metastasis. The beneficial effects of halofuginone treatment were comparable with those observed with other anti–TGF-β strategies, including systemic administration of SD208, a small-molecule inhibitor of TGF-β receptor I kinase, or forced overexpression of Smad7, a negative regulator of TGF-β signaling. Furthermore, mice with established bone metastases treated with halofuginone had significantly less osteolysis than mice receiving placebo assessed by radiography. Thus, halofuginone is also effective in reducing the progression of melanoma bone metastases. Moreover, halofuginone treatment reduced melanoma metastasis to the brain, showing the potential of this novel treatment against cancer metastasis. Cancer Res; 72(23); 6247–56. ©2012 AACR.
Adenylate Kinase-4 Is a Marker of Poor Clinical Outcomes That Promotes Metastasis of Lung Cancer by Downregulating the Transcription Factor ATF3
Authors: Jan Yi-Hua , Tsai Hong-Yuan , Yang Chih-Jen , Huang Ming-Shyan , Yang Yi-Fang , Lai Tsung-Ching , Lee Chien-Hsin , Jeng Yung-Ming , Huang Chi-Ying , Su Jen-Liang , Chuang Yung-Jen , Hsiao Michael 
Published: September 2012

Abstract
Biomarkers predicting metastatic capacity might assist the development of better therapeutic strategies for aggressive cancers such as lung cancer. In this study, we show that adenylate kinase-4 (AK4) is a progression-associated gene in human lung cancer that promotes metastasis. Analysis of published microarray data showed that AK4 was upregulated in lung adenocarcinoma compared with normal cells. High AK4 expression was associated with advanced stage, disease recurrence and poor prognosis. Loss of AK4 expression suppressed the invasive potential of lung cancer cell lines, whereas AK4 overexpression promoted invasion in vitro and in vivo. Mechanistically, the transcription factor ATF3 was identified as a pivotal regulatory target of AK4. Simultaneous reduction in AK4 and ATF3 expression abolished the inhibitory effects of ATF3 on invasion. ATF3 overexpression in AK4-overexpressing cells limits invasion activity. Furthermore, patients with high AK4 and low ATF3 expression showed unfavorable outcomes compared with patients with low AK4 and high ATF3 expression. Taken together, our findings indicated that AK4 promotes malignant progression and recurrence by promoting metastasis in an ATF3-dependent manner. Cancer Res; 72(19); 5119–29. ©2012 AACR.
Intratumor Heterogeneity: Evolution through Space and Time
Authors: Swanton Charles 
Published: September 2012

Abstract
Recent technologic advances have permitted higher resolution and more rapid analysis of individual cancer genomes at the single-nucleotide level. Such advances have shown bewildering intertumor heterogeneity with limited somatic alterations shared between tumors of the same histopathologic subtype. Exacerbating such complexity, increasing evidence of intratumor genetic heterogeneity (ITH) is emerging, both within individual tumor biopsies and spatially separated between biopsies of the same tumor. Sequential analysis of tumors has also revealed evidence that ITH temporally evolves during the disease course. ITH has implications for predictive or prognostic biomarker strategies, where the tumor subclone that may ultimately influence therapeutic outcome may evade detection because of its absence or presence at low frequency at diagnosis or because of its regional separation from the tumor biopsy site. In this review, the implications of “trunk and branch” tumor evolution for drug discovery approaches and emerging evidence that low-frequency somatic events may drive tumor growth through paracrine signaling fostering a tumor ecologic niche are discussed. The concept of an “actionable mutation” is considered within a model of clonal dominance and heterogeneous tumor cell dependencies. Evidence that cancer therapeutics may augment ITH and the need to track the tumor subclonal architecture through treatment are defined as key research areas. Finally, if combination therapeutic approaches to limit the consequences of ITH prove challenging, identification of drivers or suppressors of ITH may provide attractive therapeutic targets to limit tumor evolutionary rates and adaptation. Cancer Res; 72(19); 4875–82. ©2012 AACR.
Targeting Olfactomedin-like 3 Inhibits Tumor Growth by Impairing Angiogenesis and Pericyte Coverage
Authors: Miljkovic-Licina Marijana , Hammel Philippe , Garrido-Urbani Sarah , Lee Boris P.-L. , Meguenani Mehdi , Chaabane Chiraz , Bochaton-Piallat Marie-Luce , Imhof Beat A. 
Published: September 2012

AbstractAntiangiogenic drugs have been used as anticancer agents to target tumor endothelial cells or pericytes. Because of limited efficacy of the current monotherapies, there is a strong demand for the dual targeting of endothelial cells and pericytes. Here, we identify Olfactomedin-like 3 (Olfml3) as a novel proangiogenic cue within the tumor microenvironment. Tumor-derived Olfml3 is produced by both tumor endothelial cells and accompanying pericytes and deposited in the perivascular compartment. Blockade of Olfml3 by anti-Olfml3 antibodies is highly effective in reducing tumor vascularization, pericyte coverage, and tumor growth. In vitro, Olfml3 targeting is sufficient to inhibit endothelioma cell migration and sprouting. Olfml3 alone or through binding to BMP4 enhances the canonical SMAD1/5/8 signaling pathway required for BMP4-induced angiogenesis. Therefore, Olfml3 blockade provides a novel strategy to control tumor growth by targeting two distinct cell types within the tumor microenvironment using a single molecule. Mol Cancer Ther; 11(12); 2588–99. ©2012 AACR.
FGFR Genetic Alterations Predict for Sensitivity to NVP-BGJ398, a Selective Pan-FGFR Inhibitor
Authors: Guagnano Vito , Kauffmann Audrey , Wöhrle Simon , Stamm Christelle , Ito Moriko , Barys Louise , Pornon Astrid , Yao Yao , Li Fang , Zhang Yun , Chen Zhi , Wilson Christopher J. , Bordas Vincent , Le Douget Mickaël , Gaither L. Alex , Borawski Jason , Monahan John E. , Venkatesan Kavitha , Brümmendorf Thomas , Thomas David M. , Garcia-Echeverria Carlos , Hofmann Francesco , Sellers William R. , Graus-Porta Diana 
Published: September 2012

Abstract
Patient stratification biomarkers that enable the translation of cancer genetic knowledge into clinical use are essential for the successful and rapid development of emerging targeted anticancer therapeutics. Here, we describe the identification of patient stratification biomarkers for NVP-BGJ398, a novel and selective fibroblast growth factor receptor (FGFR) inhibitor. By intersecting genome-wide gene expression and genomic alteration data with cell line–sensitivity data across an annotated collection of cancer cell lines called the Cancer Cell Line Encyclopedia, we show that genetic alterations for FGFR family members predict for sensitivity to NVP-BGJ398. For the first time, we report oncogenic FGFR1 amplification in osteosarcoma as a potential patient selection biomarker. Furthermore, we show that cancer cell lines harboring FGF19 copy number gain at the 11q13 amplicon are sensitive to NVP-BGJ398 only when concomitant expression of β-klotho occurs. Thus, our findings provide the rationale for the clinical development of FGFR inhibitors in selected patients with cancer harboring tumors with the identified predictors of sensitivity.
Significance: The success of a personalized medicine approach using targeted therapies ultimately depends on being able to identify the patients who will benefit the most from any given drug. To this end, we have integrated the molecular profiles for more than 500 cancer cell lines with sensitivity data for the novel anticancer drug NVP-BGJ398 and showed that FGFR genetic alterations are the most significant predictors for sensitivity. This work has ultimately endorsed the incorporation of specific patient selection biomakers in the clinical trials for NVP-BGJ398. Cancer Discov; 2(12); 1118–33. ©2012 AACR.
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White Adipose Tissue Apolipoprotein C-I Secretion in Relation to Delayed Plasma Clearance of Dietary Fat in Humans
Authors: Wassef Hanny , Salem Huda , Bissonnette Simon , Baass Alexis , Dufour Robert , Davignon Jean , Faraj May 
Published: September 2012

Objective—
White adipose tissue (WAT) dysfunction is characterized by delayed clearance of dietary triglyceride-rich lipoproteins (TRL). We reported that apolipoprotein (apo) C-I, a transferable apolipoprotein that inhibits lipoprotein lipase activity when bound to TRL, was produced by a human adipocyte model. Thus, we aimed to determine whether increased WAT apoC-I secretion is related to delayed dietary fat clearance in humans.

Methods and Results—

After the ingestion of a
13
C-triolein–labeled high-fat meal, postmenopausal obese women with high-fasting WAT apoC-I secretion (median >0.81 μmol/L per g/4 hours, n=9) had delayed postprandial plasma clearance of
13
C-triglyceride and
13
C-nonesterified fatty acids over 6 hours compared with controls. WAT apoC-I secretion over 4 hours correlated with fasting total and non–high-density lipoprotein apoC-I but not with high-density lipoprotein apoC-I and was the primary predictor of 4-hour postprandial increases in TRL apoC-I. Correction for TRL apoC-I eliminated the association of WAT apoC-I with 6-hour area under the curve of plasma
13
C-triglyceride; correction for insulin sensitivity or inflammation did not. Finally, in addition to apoC-I, WAT secreted considerable amount of apoC-II, apoC-III, and apoE over 24 hours; however, only WAT apoC-I secretion was associated with 6-hour area under the curve of plasma
13
C-triglyceride.

Conclusion—
Increased WAT apoC-I secretion in obese women is associated with delayed postprandial dietary fat clearance mediated by increased TRL apoC-I. Thus, we hypothesize that reducing WAT apoC-I secretion ameliorates WAT dysfunction and associated cardiometabolic risks in humans.
Apelin/APJ Signaling Is a Critical Regulator of Statin Effects in Vascular Endothelial Cells—Brief Report
Authors: McLean Danielle L. , Kim Jongmin , Kang Yujung , Shi Hong , Atkins G. Brandon , Jain Mukesh K. , Chun Hyung J. 
Published: September 2012

Objective—
The endothelial response elicited by the G-protein−coupled receptor pathway involving apelin and APJ predicts an overall vasoprotective effect. As a number of downstream endothelial targets of apelin/APJ signaling are also known to be targeted by statins (3-hydroxy-3-methyl-glutaryl [HMG]-CoA reductase inhibitors) as potential mediators of their known pleiotropic effects, we evaluated for the involvement of apelin/APJ signaling in statin endothelial effects.

Methods and Results—
We found that disruption of apelin/APJ signaling in endothelial cells leads to significantly decreased expression of Krűppel-like factor 2, endothelial nitric oxide synthase, and thrombomodulin. We found that statin-mediated induction of Krűppel-like factor 2, endothelial nitric oxide synthase, and thrombomodulin expression, as well as inhibition of monocyte-endothelial adhesion, was abrogated by concurrent apelin knockdown. Moreover, we found that statins can transcriptionally regulate APJ in a Krűppel-like factor 2−dependent manner, demonstrating the presence of a positive-feedback loop.

Conclusion—
Our findings provide a novel mechanism by which the apelin/APJ pathway serves as a critical intermediary that links statin to its pleiotropic effects in regulating endothelial gene targets and function.
Addition of Inflammatory Biomarkers Did Not Improve Diabetes Prediction in the Community: The Framingham Heart Study
Authors: Dallmeier Dhayana , Larson Martin G. , Wang Na , Fontes João D. , Benjamin Emelia J. , Fox Caroline S. 
Published: September 2012

Background

Prior studies have reported conflicting findings with regard to the association of biomarkers in the prediction of incident type 2 diabetes. We evaluated 12 biomarkers as possible diabetes predictors in the
F
ramingham
H
eart
S
tudy.

Methods and Results

Biomarkers representing inflammation (
C
‐reactive protein, interleukin‐6, monocyte chemoattractant protein‐1, tumor necrosis factor receptor 2, osteoprotegerin, and fibrinogen), endothelial dysfunction (intercellular adhesion molecule‐1), vascular damage (
CD
40‐ligand,
P
‐selectin, and lipoprotein‐associated phospholipase A2 mass and activity), and oxidative stress (urinary isoprostanes) were measured in participants without diabetes attending the Offspring seventh (n=2499) or multiethnic Omni second (n=189) examination (1998–2001). Biomarkers were log
e
transformed and standardized. Multivariable logistic regression tested each biomarker in association with incident diabetes at a follow‐up examination (the Offspring eighth and Omni third examination; mean 6.6 years later), with adjustment for age, sex, cohort, body mass index, fasting glucose, systolic blood pressure, high‐density lipoprotein cholesterol, triglycerides, and smoking.

C

statistics were evaluated with and without inflammatory markers. In 2638 participants (56% women, mean age 59 years), 162 (6.1%) developed type 2 diabetes. All biomarkers, excluding osteoprotegerin, were associated with the outcome with adjustment for age, sex, and cohort; however, none remained significant after multivariable adjustment (all
P
>0.05). The
c
statistic from the model including only clinical covariates (0.89) did not statistically significantly improve after addition of biomarkers (all
P
>0.10).

Conclusions
Biomarkers representing different inflammatory pathways are associated with incident diabetes but do not remain statistically significant after adjustment for established clinical covariates. Inflammatory biomarkers might not be an effective resource to predict type 2 diabetes in community‐based samples.
Therapeutic Lymphangiogenesis With Implantation of Adipose‐Derived Regenerative Cells
Authors: Shimizu Yuuki , Shibata Rei , Shintani Satoshi , Ishii Masakazu , Murohara Toyoaki 
Published: September 2012

Background
Lymphedema is one of the serious clinical problems that can occur after surgical resection of malignant tumors such as breast cancer or intra‐pelvic cancers. However, no effective treatment options exist at present. Here, we report that implantation of adipose‐derived regenerative cells (ADRCs) can induce lymphangiogenesis in a mouse model of reparative lymphedema.

Methods and Results

ADRCs were isolated from C57BL/6J mice. To examine the therapeutic efficacy of ADRC implantation in vivo, we established a new mouse model of tail lymphedema. Lymphedema was improved significantly by local injection of ADRCs (
P
<0.05). Histological analysis revealed that lymphatic capillary density was greater in the ADRC group than in the phosphate‐buffered saline control group (
P
<0.01). Tissue expression of vascular endothelial growth factor C mRNA and plasma levels of vascular endothelial growth factor C were greater in the ADRC group than in the control group (
P
<0.01 and
P
<0.05, respectively). ADRCs released vascular endothelial growth factor C, which directly stimulated lymphangiogenesis. Implantation of ADRCs also enhanced recruitment of bone marrow–derived M2 macrophages, which served as lymphatic endothelial progenitor cells.

Conclusions

Implantation of autologous ADRCs could be a useful treatment option for patients with severe lymphedema via mediation of lymphangiogenesis.

(
J Am Heart Assoc
. 2012;1:e000877 doi: 10.1161/JAHA.112.000877.)