bluuebunny/crossref_metadata_2025 huggingface dataset:
Reworking of old continental lithosphere: an important crustal evolution mechanism in orogenic belts, as evidenced by Triassic I-type granitoids in the East Kunlun orogen, Northern Tibetan Plateau
Authors: Xiong Fuhao , Ma Changqian , Zhang Jinyang , Liu Bin , Jiang Hong’an
Published: June 2014

There is a strong genetic relationship between the petrogenesis of I-type granitoids and the evolution of continental crust in orogenic belts. This study of I-type granitoids in the East Kunlun orogen, Northern Tibetan Plateau, shows that reworking of old continental lithosphere is an important key to this genetic relationship. The East Kunlun has numerous Triassic granitic plutons that are related to subduction of the Palaeo-Tethyan ocean and terrane collision in the early Mesozoic. U–Pb analysis of zircons from these Triassic granitoids indicates that the granitic magmatism lasted from 249 to 223 Ma. Based on elemental and isotopic compositions and their petrogenesis, the magmatism can be divided into three groups. (1) Group 1 consists of quartz diorites and granodiorites (241–249 Ma), which are metaluminous high-K calc-alkaline I-type granitoids and exhibit typical subduction-related chemical characteristics. They were derived from lower crust mainly composed of Precambrian metabasaltic basement rocks with different degrees of involvement of mantle material. (2) Group 2 consists of granitic porphyries and syenogranites (231–238 Ma), which are high Rb/Sr, metaluminous to weakly peraluminous high-K alkali-calcic I-type granitoids, showing characteristics of typical pure crustal-derived granitoids. They were derived from partial melting of a Mesoproterozoic metagreywacke source in the lower crust. (3) Group 3 consists of porphyry granodiorites (
c
. 223 Ma), which are metaluminous high-K calc-alkaline I-type granitoids and exhibit the typical geochemical characteristics of adakites (e.g. high La/Yb and Sr/Y ratios and low Y and Yb contents). Their high K
2
O and low Mg# with evolved Sr–Nd–Hf isotopic compositions indicate that they were most probably derived from thickened mafic lower continental crust, which underwent partial melting induced by underplated hot mafic magma. Combining the present work with previous studies, we propose that the subduction of the Palaeo-Tethyan ocean lasted from 278 to 241 Ma, and the collision between the Bayan Har terrane and the East Kunlun occurred at 231–238 Ma, whereas the group 3 granitoids most probably formed in a post-collisional setting. Overall, all the studied I-type granitoids were derived from partial melting of old continental lower crust with minor addition of lithospheric mantle material; thus reworking of old continental lithosphere is an important mechanism for the evolution of orogenic crust.

Supplementary materials:

Analytical methods, zircon U–Pb data, geochemical data, and Sr–Nd–Hf isotope data for the granitoids are available at
www.geolsoc.org.uk/SUP18758
.
All hands on deck!
Authors: Woo Grace
Published: June 2014

Ten action items for attracting and retaining more women in science, technology, engineering, and mathematics fields of study.
Gendered expectations
Authors: Fine Eve , Wendt Amy , Carnes Molly
Published: June 2014

A look at how implicit biases influence the advancement of women in science and engineering.
The curious case of a sick google glass
Authors: Richter Wolfgang
Published: June 2014

The
XRDS
blog highlights a range of topics from security and privacy to neuroscience. Selected blog posts, edited for print, will be featured in every issue. Please visit xrds.acm.org/blog to read each post in its entirety.
A micromechanical model for estimating alveolar wall strain in mechanically ventilated edematous lungs
Authors: Chen Zheng-long , Chen Ya-zhu , Hu Zhao-yan
Published: June 2014

To elucidate the micromechanics of pulmonary edema has been a significant medical concern, which is beneficial to better guide ventilator settings in clinical practice. In this paper, we present an adjoining two-alveoli model to quantitatively estimate strain and stress of alveolar walls in mechanically ventilated edematous lungs. The model takes into account the geometry of the alveolus, the effect of surface tension, the length-tension properties of parenchyma tissue, and the change in thickness of the alveolar wall. On the one hand, our model supports experimental findings (Perlman CE, Lederer DJ, Bhattacharya J. Am J Respir Cell Mol Biol 44: 34–39, 2011) that the presence of a liquid-filled alveolus protrudes into the neighboring air-filled alveolus with the shared septal strain amounting to a maximum value of 1.374 (corresponding to the maximum stress of 5.12 kPa) even at functional residual capacity; on the other hand, it further shows that the pattern of alveolar expansion appears heterogeneous or homogeneous, strongly depending on differences in air-liquid interface tension on alveolar segments. The proposed model is a preliminary step toward picturing a global topographical distribution of stress and strain on the scale of the lung as a whole to prevent ventilator-induced lung injury.
Range of motion, neuromechanical, and architectural adaptations to plantar flexor stretch training in humans
Authors: Blazevich A. J. , Cannavan D. , Waugh C. M. , Miller S. C. , Thorlund J. B. , Aagaard P. , Kay A. D.
Published: June 2014

The neuromuscular adaptations in response to muscle stretch training have not been clearly described. In the present study, changes in muscle (at fascicular and whole muscle levels) and tendon mechanics, muscle activity, and spinal motoneuron excitability were examined during standardized plantar flexor stretches after 3 wk of twice daily stretch training (4 × 30 s). No changes were observed in a nonexercising control group ( n = 9), however stretch training elicited a 19.9% increase in dorsiflexion range of motion (ROM) and a 28% increase in passive joint moment at end ROM ( n = 12). Only a trend toward a decrease in passive plantar flexor moment during stretch (−9.9%; P = 0.15) was observed, and no changes in electromyographic amplitudes during ROM or at end ROM were detected. Decreases in Hmax:Mmax(tibial nerve stimulation) were observed at plantar flexed (gastrocnemius medialis and soleus) and neutral (soleus only) joint angles, but not with the ankle dorsiflexed. Muscle and fascicle strain increased (12 vs. 23%) along with a decrease in muscle stiffness (−18%) during stretch to a constant target joint angle. Muscle length at end ROM increased (13%) without a change in fascicle length, fascicle rotation, tendon elongation, or tendon stiffness following training. A lack of change in maximum voluntary contraction moment and rate of force development at any joint angle was taken to indicate a lack of change in series compliance of the muscle-tendon unit. Thus, increases in end ROM were underpinned by increases in maximum tolerable passive joint moment (stretch tolerance) and both muscle and fascicle elongation rather than changes in volitional muscle activation or motoneuron pool excitability.
Exercise training and artery function in humans: nonresponse and its relationship to cardiovascular risk factors
Authors: Green Daniel J. , Eijsvogels Thijs , Bouts Yvette M. , Maiorana Andrew J. , Naylor Louise H. , Scholten Ralph R. , Spaanderman Marc E. A. , Pugh Christopher J. A. , Sprung Victoria S. , Schreuder Tim , Jones Helen , Cable Tim , Hopman Maria T. E. , Thijssen Dick H. J.
Published: June 2014

The objectives of our study were to examine 1) the proportion of responders and nonresponders to exercise training in terms of vascular function; 2) a priori factors related to exercise training-induced changes in conduit artery function, and 3) the contribution of traditional cardiovascular risk factors to exercise-induced changes in artery function. We pooled data from our laboratories involving 182 subjects who underwent supervised, large-muscle group, endurance-type exercise training interventions with pre-/posttraining measures of flow-mediated dilation (FMD%) to assess artery function. All studies adopted an identical FMD protocol (5-min ischemia, distal cuff inflation), contemporary echo-Doppler methodology, and observer-independent automated analysis. Linear regression analysis was used to identify factors contributing to changes in FMD%. We found that cardiopulmonary fitness improved, and weight, body mass index (BMI), cholesterol, and mean arterial pressure (MAP) decreased after training, while FMD% increased in 76% of subjects ( P < 0.001). Training-induced increase in FMD% was predicted by lower body weight (β = −0.212), lower baseline FMD% (β = −0.469), lower training frequency (β = −0.256), and longer training duration (β = 0.367) (combined: P < 0.001, r = 0.63). With the exception of a modest correlation with total cholesterol ( r = −0.243, P < 0.01), changes in traditional cardiovascular risk factors were not significantly related to changes in FMD% ( P > 0.05). In conclusion, we found that, while some subjects do not demonstrate increases following exercise training, improvement in FMD% is present in those with lower pretraining body weight and endothelial function. Moreover, exercise training-induced change in FMD% did not correlate with changes in traditional cardiovascular risk factors, indicating that some cardioprotective effects of exercise training are independent of improvement in risk factors.
Microbiota Modulate Tumoral Immune Surveillance in Lung through a γδT17 Immune Cell-Dependent Mechanism
Authors: Cheng Min , Qian Liting , Shen Guodong , Bian Geng , Xu Tingjuan , Xu Weiping , Shen Gan , Hu Shilian
Published: June 2014

Commensal bacteria are crucial to maintain immune homeostasis in mucosal tissues and disturbances in their ecology can affect disease susceptibility. Here, we report evidence that commensal bacteria shape the efficiency of immune surveillance in mucosal tissues. Antibiotic-treated (Abt) mice were more susceptible to development of engrafted B16/F10 melanoma and Lewis lung carcinoma, exhibiting a shortened mean survival time with more numerous and larger tumor foci in the lungs. The defective antitumor response of Abt mice was independent of dehydration caused by antibiotics. Host defenses relied upon intact commensal bacteria with no class specificity. Mechanistic investigations revealed a defective induction of the γδT17 cell response in lungs of Abt mice; here, more aggressive tumor development was observed, possibly related to a reduction in IL6 and IL23 expression there. Adding normal γδT cells or supplementing IL17 restored the impaired immune surveillance phenotype in Abt mice. Overall, our results demonstrated the importance of commensal bacteria in supporting the host immune response against cancer, defined an important role for γδT17 responses in the mechanism, and suggested deleterious effects of antibiotic treatment on cancer susceptibility and progression. Cancer Res; 74(15); 4030–41. ©2014 AACR.
Human Brat Ortholog TRIM3 Is a Tumor Suppressor That Regulates Asymmetric Cell Division in Glioblastoma
Authors: Chen Gang , Kong Jun , Tucker-Burden Carol , Anand Monika , Rong Yuan , Rahman Fahmia , Moreno Carlos S. , Van Meir Erwin G. , Hadjipanayis Constantinos G. , Brat Daniel J.
Published: June 2014

Cancer stem cells, capable of self-renewal and multipotent differentiation, influence tumor behavior through a complex balance of symmetric and asymmetric cell divisions. Mechanisms regulating the dynamics of stem cells and their progeny in human cancer are poorly understood. In Drosophila, mutation of brain tumor (brat) leads to loss of normal asymmetric cell division by developing neural cells and results in a massively enlarged brain composed of neuroblasts with neoplastic properties. Brat promotes asymmetric cell division and directs neural differentiation at least partially through its suppression on Myc. We identified TRIM3 (11p15.5) as a human ortholog of Drosophila brat and demonstrate its regulation of asymmetric cell division and stem cell properties of glioblastoma (GBM), a highly malignant human brain tumor. TRIM3 gene expression is markedly reduced in human GBM samples, neurosphere cultures, and cell lines and its reconstitution impairs growth properties in vitro and in vivo. TRIM3 expression attenuates stem-like qualities of primary GBM cultures, including neurosphere formation and the expression of stem cell markers CD133, Nestin, and Nanog. In GBM stem cells, TRIM3 expression leads to a greater percentage dividing asymmetrically rather than symmetrically. As with Brat in Drosophila, TRIM3 suppresses c-Myc expression and activity in human glioma cell lines. We also demonstrate a strong regulation of Musashi–Notch signaling by TRIM3 in GBM neurospheres and neural stem cells that may better explain its effect on stem cell dynamics. We conclude that TRIM3 acts as a tumor suppressor in GBM by restoring asymmetric cell division. Cancer Res; 74(16); 4536–48. ©2014 AACR.
Acquired Resistance to Endocrine Treatments Is Associated with Tumor-Specific Molecular Changes in Patient-Derived Luminal Breast Cancer Xenografts
Authors: Cottu Paul , Bièche Ivan , Assayag Franck , El Botty Rania , Chateau-Joubert Sophie , Thuleau Aurélie , Bagarre Thomas , Albaud Benoit , Rapinat Audrey , Gentien David , de la Grange Pierre , Sibut Vonick , Vacher Sophie , Hatem Rana , Servely Jean-Luc , Fontaine Jean-Jacques , Decaudin Didier , Pierga Jean-Yves , Roman-Roman Sergio , Marangoni Elisabetta
Published: June 2014

Purpose: Patients with luminal breast cancer (LBC) often become endocrine resistant over time. We investigated the molecular changes associated with acquired hormonoresistances in patient-derived xenografts of LBC.

Experimental Design: Two LBC xenografts (HBCx22 and HBCx34) were treated with different endocrine treatments (ET) to obtain xenografts with acquired resistances to tamoxifen (TamR) and ovariectomy (OvaR). PI3K pathway activation was analyzed by Western blot analysis and IHC and responses to ET combined to everolimus were investigated in vivo. Gene expression analyses were performed by RT-PCR and Affymetrix arrays.

Results: HBCx22 TamR xenograft was cross-resistant to several hormonotherapies, whereas HBCx22 OvaR and HBCx34 TamR exhibited a treatment-specific resistance profile. PI3K pathway was similarly activated in parental and resistant xenografts but the addition of everolimus did not restore the response to tamoxifen in TamR xenografts. In contrast, the combination of fulvestrant and everolimus induced tumor regression in vivo in HBCx34 TamR, where we found a cross-talk between the estrogen receptor (ER) and PI3K pathways. Expression of several ER-controlled genes and ER coregulators was significantly changed in both TamR and OvaR tumors, indicating impaired ER transcriptional activity. Expression changes associated with hormonoresistance were both tumor and treatment specific and were enriched for genes involved in cell growth, cell death, and cell survival.

Conclusions: PDX models of LBC with acquired resistance to endocrine therapies show a great diversity of resistance phenotype, associated with specific deregulations of ER-mediated gene transcription. These models offer a tool for developing anticancer therapies and to investigate the dynamics of resistance emerging during pharmacologic interventions. Clin Cancer Res; 20(16); 4314–25. ©2014 AACR.
Complex Disease–, Gene–, and Drug–Drug Interactions: Impacts of Renal Function, CYP2D6 Phenotype, and OCT2 Activity on Veliparib Pharmacokinetics
Authors: Li Jing , Kim Seongho , Sha Xianyi , Wiegand Richard , Wu Jianmei , LoRusso Patricia
Published: June 2014

Purpose: Veliparib, a poly (ADP-ribose) polymerase (PARP) inhibitor, undergoes renal excretion and liver metabolism. This study quantitatively assessed the interactions of veliparib with metabolizing enzyme (CYP2D6) and transporter (OCT2) in disease settings (renal impairment).

Experimental Design: Veliparib in vitro metabolism was examined in human liver microsomes and recombinant enzymes carrying wild-type CYP2D6 or functional defect variants (CYP2D6*10 and *4). Plasma pharmacokinetics were evaluated in 27 patients with cancer. A parent–metabolite joint population model was developed to characterize veliparib and metabolite (M8) pharmacokinetics and to identify patient factors influencing veliparib disposition. A physiologically based pharmacokinetic model integrated with a mechanistic kidney module was developed to quantitatively predict the individual and combined effects of renal function, CYP2D6 phenotype, and OCT2 activity on veliparib pharmacokinetics.

Results: In vitro intrinsic clearance of CYP2D6.1 and CYP2D6.10 for veliparib metabolism were 0.055 and 0.017 μL/min/pmol CYP, respectively. Population mean values for veliparib oral clearance and M8 clearance were 13.3 and 8.6 L/h, respectively. Creatinine clearance was identified as the significant covariate on veliparib oral clearance. Moderate renal impairment, CYP2D6 poor metabolizer, and co-administration of OCT2 inhibitor (cimetidine) increased veliparib steady-state exposure by 80%, 20%, and 30%, respectively. These factors collectively led to >2-fold increase in veliparib exposure.

Conclusions: Renal function (creatinine clearance) is a significant predictor for veliparib exposure in patients with cancer. Although a single factor (i.e., renal impairment, CYP2D6 deficiency, and reduced OCT2 activity) shows a moderate impact, they collectively could result in a significant and potentially clinically relevant increase in veliparib exposure. Clin Cancer Res; 20(15); 3931–44. ©2014 AACR.
The Endourological Treatment of Renal Matrix Stones
Authors: Beltrami Paolo , Ruggera Lorenzo , Guttilla Andrea , Iannetti Alessandro , Zattoni Fabio , Gigli Francesca , Bernich Patrizia , Zattoni Filiberto
Published: June 2014

Objective: To report our experience with the endourological treatment of renal matrix stones, an infrequent form of urinary calculi whose diagnosis and treatment are often difficult. Methods: From 1990 to 2010 we treated 9 female patients with matrix calculi using the endourological approach; 4 presented with renal colics, 3 with symptomatic urinary tract infection and 2 with asymptomatic bacteriuria. Six patients underwent percutaneous lithotripsy and 3 retrograde intrarenal surgery as first-line therapy. Three cases needed a multidisciplinary approach. Results: The six percutaneous procedures were successful after a single session, while the retrograde approach required multiple treatments; a single case needed a shock wave session to complete the fragmentation, in another one a percutaneous lithotripsy was necessary after the first procedure, and a third case needed multidisciplinary treatment. Conclusions: Percutaneous lithotripsy has been confirmed as the first option for matrix stones. The retrograde approach - by confirming the suspected diagnosis and being minimally invasive - may be employed to treat either lower-size stones or stones at high risk of recurrence.
BAC Chromosomal Microarray for Prenatal Detection of Chromosome Anomalies in Fetal Ultrasound Anomalies: An Economic Evaluation
Authors: Hillman Sarah C. , Barton Pelham M. , Roberts Tracy E. , Maher Eamonn R. , McMullan Dominic M. , Kilby Mark D.
Published: June 2014

Introduction: To determine the cost-effectiveness of prenatal chromosomal microarray (CMA) when performed for structural anomalies on fetal ultrasound scan over conventional techniques. Method: A decision tree was populated using data from a prospective cohort of women undergoing testing when a fetal ultrasound scan showed a structural abnormality. Nine strategies of testing were modeled including combinations of the tests: QFPCR, G-band karyotyping, CMA and FISH for DiGeorge (22q) microdeletion. Results: When CMA costs GBP 405 and using a 1-Mb BAC array it would cost GBP 24,600 for every additional case detected by CMA over a combination of QFPCR, followed by G-band karyotype, followed lastly by FISH (for DiGeorge syndrome). If CMA is performed instead of conventional karyotyping alone it costs GBP 33,000 for every additional case detected. However, if the cost of CMA is reduced to GBP 360 than when CMA is performed instead of conventional karyotyping alone it would cost GBP 9,768 for every additional case detected. Discussion: The use of a prenatal BAC CMA is not currently cost-effective when compared to other testing strategies. However, as CMA costs decrease and resolution (and detection rates) increase it is likely to become the cost-effective option of the future.
Intentions to Donate to a Biobank in a National Sample of African Americans
Authors: McDonald Jasmine A. , Vadaparampil Susan , Bowen Deborah , Magwood Gayenell , Obeid Jihad S. , Jefferson Melanie , Drake Richard , Gebregziabher Mulugeta , Hughes Halbert Chanita
Published: June 2014

Background/Aims: Despite the investments being made to develop biobanks, African Americans are under-represented in genomic studies. We identified factors having significant independent associations with intentions to donate personal health information and blood and/or tissue samples to a biobank in a national random sample of African Americans (n = 1,033). Methods: We conducted a national survey from October 2010 through February 2011. Results: Twenty-three percent of respondents reported that it was not at all likely that they would donate to a biobank, 18% reported it was a little likely, 36% reported it was somewhat likely, and 23% reported it was very likely. Respondents who were likely to donate to a biobank had greater positive expectations about participating in cancer genetics research and reported more participation facilitators relative to barriers. Respondents who were distrustful of researchers had a significantly lower likelihood of being willing to donate to a biobank compared to those who were less distrustful. Conclusions: African Americans have diverse attitudes about participating in genetics research, and many are likely to donate to a biobank based on expectations of positive outcomes. It may be important to address attitudes about genetics research as part of recruitment to enhance the quality of informed consent for participation in biobanks among African Americans.
The 21-Gene Recurrence Score Assay (Oncotype DX™) in Estrogen Receptor-Positive Male Breast Cancer: Experience in an Israeli Cohort
Authors: Grenader Tal , Yerushalmi Rinat , Tokar Margarita , Fried Georgeta , Kaufman Bella , Peretz Tamar , Geffen David B.
Published: June 2014

Objective: The 21-gene recurrence score (RS) assay has been widely adopted for use in early estrogen receptor (ER)-positive breast cancer to assess the risk for distant recurrence and the potential benefit of adjuvant chemotherapy. The primary aim of this study was to assess RS distribution in Israeli male breast cancer (MBC) patients. Methods: The study population included 65 newly diagnosed Israeli MBC patients. Clinical and pathologic data were collected at the time of referral. Pathologic examinations were conducted at the pathology departments of the referring centers. The RS assay (Oncotype DX™) was performed on paraffin-embedded tumor samples at Genomic Health laboratories. Results: The mean age of the patients was 65.1 years (range 38-88 years). Low-risk (RS <18), intermediate-risk (RS 18-30) and high-risk (RS ≥31) scores were noted in 29 patients (44.6%), 27 patients (41.5%) and 9 patients (13.9%), respectively. The distribution of RS in male patients was similar to the distribution in 2,455 female patients from Israel referred during the same time period. Conclusion: Our data suggest that the distribution of Oncotype DX RS in ER-positive MBC patients is similar to that of female breast cancer patients.
Patients' Preferences for Gonadotrophin-Releasing Hormone Analogs in in vitro Fertilization
Authors: van den Wijngaard Lotte , van Wely Madelon , Dancet Eline A.F. , van Mello Nora M. , Koks Carolien A.M. , van der Veen Fulco , Mol Ben W.J. , Mochtar Monique H.
Published: June 2014

Background: Gonadotrophin-releasing hormone (GnRH) antagonists reduce ovarian hyperstimulation syndrome (OHSS) at the price of a small reduction in effectiveness compared to GnRH agonists. The aim of this study was to investigate patients' preferences on effectiveness, safety and burden of GnRH analogs. Methods: A discrete choice experiment (DCE) and a trade-off question were designed. Patients embarking on assisted reproductive technique treatment were asked to choose between two hypothetical medications which differed in effectiveness, safety and burden. Results: A total of 172 questionnaires were analyzed. All attributes of the DCE had a statistically significant impact on the preference of the respondents. Respondents were willing to trade off 0.87 and 0.81% effectiveness for a decrease in OHSS risk and for fewer side effects, respectively. Respondents were not willing to trade off effectiveness for ‘importance of compliance' (trade-off 0.40%) or a shorter ‘duration of treatment' (trade-off 0.26%). The trade-off questions showed that already at a 2.0% increase in pregnancy rate in favor of the agonists, the majority of the respondents changed their preference from antagonists to agonists (2.0%, 95% CI 1.7-2.1). Conclusion: Safety and burden are important to patients, but are not important enough to make up for a small decrease in pregnancy rate.
The Transcription Factor Nuclear Factor of Activated T Cells c3 Modulates the Function of Macrophages in Sepsis
Authors: Ranjan Ravi , Deng Jing , Chung Sangwoon , Lee Yong Gyu , Park Gye Young , Xiao Lei , Joo Myungsoo , Christman John William , Karpurapu Manjula
Published: June 2014

The role of the transcription factor nuclear factor of activated T cells (NFAT) was initially identified in T and B cell gene expression, but its role in regulating gene expression in macrophages during sepsis is not known. Our data show that NFATc3 regulates expression of inducible nitric oxide synthase (iNOS) in macrophages stimulated with lipopolysaccharide. Selective inhibition of NFAT by cyclosporine A and a competitive peptide inhibitor 11R-VIVIT inhibited endotoxin-induced expression of iNOS and nitric oxide (NO) release. Macrophages from NFATc3 knockout (KO) mice show reduced iNOS expression and NO release and attenuated bactericidal activity. Gel shift and chromatin immunoprecipitation assays show that endotoxin challenge increases NFATc3 binding to the iNOS promoter, resulting in transcriptional activation of iNOS. The binding of NFATc3 to the iNOS promoter is abolished by NFAT inhibitors. NFATc3 KO mice subjected to sepsis show that NFATc3 is necessary for bacterial clearance in mouse lungs during sepsis. Our study demonstrates for the first time that NFATc3 is necessary for macrophage iNOS expression during sepsis, which is essential for containment of bacterial infections.
Cytotechnologist Performance for Detecting Nuclear Atypia in Indeterminate Thyroid Fine Needle Aspirates
Authors: VandenBussche Christopher J. , Adams Christina , Ali Syed Z. , Olson Matthew T.
Published: June 2014

Introduction: The thyroid gland is arguably the fastest growing anatomic site for fine needle aspiration (FNA). With the increase of thyroid cases, a reevaluation of cytotechnologist screening quality metrics in terms of thyroid FNA is called for. We present our institutional cytotechnologist performance at screening for nuclear atypia by applying established quality metrics. Materials and Methods: Information on 8,814 consecutive thyroid cytopathology cases over a 10-year period was retrieved from computerized records. A subsample of cases categorized either as atypia of uncertain significance with nuclear atypia or suspicious for malignancy with features suspicious for papillary thyroid carcinoma. The cytotechnologist and cytopathologist diagnoses were compared using step discrepancies and Δ-ratios. Results: Overall discrepancy between the cytotechnologist and cytopathologist diagnoses existed in <10% of all thyroid cases. One-category discrepancies were the most common (7.8%), while two-category discrepancies were rare (0.5%). The one-category discrepancy rate correlated with cytotechnologist experience. One-category undercalls were twice as common as overcalls (5.3 vs. 2.5%, p < 0.0001). Conclusions: We identified a high level of quality in the screening for nuclear atypia in thyroid FNA. The one-category discrepancy rate is suited to tracking individual cytotechnologist performance, identifies outliers and appears to correlate with cytotechnologist experience.
Randomized Controlled Trials in Very Preterm Infants: Does Inclusion in the Study Result in Any Long-Term Benefit?
Authors: Rüegger Christoph M. , Kraus Andrea , Koller Brigitte , Natalucci Giancarlo , Latal Beatrice , Waldesbühl Etienne , Fauchère Jean-Claude , Held Leonhard , Bucher Hans Ulrich
Published: June 2014

Background: Since the introduction of randomized controlled trials (RCT) in clinical research, there has been discussion of whether enrolled patients have worse or better outcomes than comparable non-participants. Objective: To investigate whether very preterm infants randomized to a placebo group in an RCT have equivalent neurodevelopmental outcomes to infants who were eligible but not randomized (eligible NR). Methods: In the course of an RCT investigating the neuroprotective effect of early high-dose erythropoietin on the neurodevelopment of very preterm infants, the outcome data of 72 infants randomized to placebo were retrospectively compared with those of 108 eligible NR infants. Our primary outcome measures were the mental (MDI) and psychomotor (PDI) developmental indices of the Bayley Scales of Infant Development II at 24 months of corrected age. The outcomes of the two groups were considered equivalent if the confidence intervals (CIs) of their mean differences fitted within our ±5-point margin of equivalence. Results: Except for a higher socioeconomic status of the trial participants, both groups were balanced for most perinatal variables. The mean difference (90% CI) between the eligible NR and the placebo group was -2.1 (-6.1 and 1.9) points for the MDI and -0.8 (-4.2 and 2.5) points for the PDI. After adjusting for the socioeconomic status, maternal age and child age at follow-up, the mean difference for the MDI was -0.5 (-4.3 and 3.4) points. Conclusions: Our results indicate that the participation of very preterm infants in an RCT is associated with equivalent long-term outcomes compared to non-participating infants.
The Silencing of N-myc Downstream-Regulated Gene-1 in an Orthotopic Pancreatic Cancer Model Leads to More Aggressive Tumor Growth and Metastases
Authors: Kim-Fuchs Corina , Winterhalder Sebastian , Winter Annja , Malinka Thomas , Born Diana , Schäfer Stephan , Stroka Deborah , Gloor Beat , Candinas Daniel , Angst Eliane
Published: June 2014

Background: The understanding of molecular mechanisms leading to poor prognosis in pancreatic cancer may help develop treatment options. N-myc downstream-regulated gene-1 (NDRG1) has been correlated to better prognosis in pancreatic cancer. Therefore, we thought to analyze how the loss of NDRG1 affects progression in an orthotopic xenograft animal model of recurrence. Methods: Capan-1 cells were silenced for NDRG1 (Csil) or transfected with scrambled shRNA (Cscr) and compared for anchorage-dependent and anchorage-independent growth, invasion and tube formation in vitro. In an orthotopic xenograft model of recurrence tumors were grown in the pancreatic tail. The effect of NDRG1 silencing was evaluated on tumor size and metastasis. Results: The silencing of NDRG1 in Capan-1 cells leads to more aggressive tumor growth and metastasis. We found faster cell growth, double count of invaded cells and 1.8-fold increase in tube formation in vitro. In vivo local tumors were 5.9-fold larger (p = 0.006) and the number of metastases was higher in animals with tumors silenced for NDRG1 primarily (3 vs. 1.1; p = 0.005) and at recurrence (3.3 vs. 0.9; p = 0.015). Conclusion: NDRG1 may be an interesting therapeutic target as its silencing in human pancreatic cancer cells leads to a phenotype with more aggressive tumor growth and metastasis.
Spinal Cord Infarction and Patent Foramen Ovale: Is There a Link
Authors: Mendonça Marcelo , Correia Ana Sofia , Luís Ana , Soares Pedro , Calado Sofia , Viana-Baptista Miguel
Published: June 2014

Spinal cord infarction (SCI) is an uncommon but important cause of acute myelopathy. Nevertheless, contrary to cerebral stroke, the discussion about paradoxical embolism as a cause of cryptogenic SCI remains dubious. We describe the case of a 24-year-old woman who developed sudden-onset back pain followed by upper limb paralysis. T2-weighted MRI demonstrated hyperintense signal, extending from C5 to D1 with corresponding restricted diffusion on diffusion-weighted MRI and reduction of the apparent diffusion coefficient. Diagnostic workup, including lumbar puncture, showed no changes. Transcranial Doppler showed a right-to-left shunt with an uncountable number of microembolic signals after Valsalva maneuvers, and a patent foramen ovale (PFO) with an atrial septum aneurysm was identified. We discuss the paucity of evidence of right-to-left shunting in spinal diseases compared to cerebral events and the potential role of paradoxical embolism through PFO as a possible mechanism of SCI.
Factor XI Regulates Pathological Thrombus Formation on Acutely Ruptured Atherosclerotic Plaques
Authors: van Montfoort Maurits L. , Kuijpers Marijke J.E. , Knaup Véronique L. , Bhanot Sanjay , Monia Brett P. , Roelofs Joris J.T.H. , Heemskerk Johan W.M. , Meijers Joost C.M.
Published: June 2014

Objective—

Coagulation factor XI is proposed as therapeutic target for anticoagulation. However, it is still unclear whether the antithrombotic properties of factor XI inhibitors influence atherosclerotic disease and atherothrombosis. Our aim is to investigate whether factor XI antisense oligonucleotides could prevent thrombus formation on acutely ruptured atherosclerotic plaques.

Approach and Results—

Atherosclerotic plaques in the carotid arteries of
Apoe
−/−
mice were acutely ruptured using ultrasound. The subsequent thrombus formation was visualized and quantified by intravital microscopy and immunohistochemistry. Mice were pretreated with either factor XI antisense or nonsense oligonucleotides (50 mg/kg) to lower factor XI plasma levels. A tail bleeding assay was used to determine the safety. On plaque rupture, initial platelet adhesion and platelet plug formation were not impaired in animals treated with factor XI antisense oligonucleotides. However, the ensuing thrombus formation and fibrin deposition were significantly lower after 5 to 10 minutes (
P
<0.05) in factor XI antisense oligonucleotide–treated animals without inducing a bleeding tendency. Furthermore, thrombi from antisense-treated animals were less stable than thrombi from placebo-treated animals. Moreover, macrophage infiltration and collagen deposition were lower in the carotid arteries of factor XI antisense–treated animals. No neutrophils were present.

Conclusions—

Factor XI antisense oligonucleotides safely prevent thrombus formation on acutely ruptured atherosclerotic plaques in mice. Furthermore, perturbed carotid arteries from factor XI antisense–treated animals show a less severe inflammatory response.
Macrophage-Independent Regulation of Reverse Cholesterol Transport by Liver X Receptors
Authors: Breevoort Sarah R. , Angdisen Jerry , Schulman Ira G.
Published: June 2014

Objective—

The ability of high-density lipoprotein (HDL) particles to accept cholesterol from peripheral cells, such as lipid-laden macrophages, and to transport cholesterol to the liver for catabolism and excretion in a process termed reverse cholesterol transport (RCT) is thought to underlie the beneficial cardiovascular effects of elevated HDL. The liver X receptors (LXRs; LXRα and LXRβ) regulate RCT by controlling the efflux of cholesterol from macrophages to HDL and the excretion, catabolism, and absorption of cholesterol in the liver and intestine. Importantly, treatment with LXR agonists increases RCT and decreases atherosclerosis in animal models. Nevertheless, LXRs are expressed in multiple tissues involved in RCT, and their tissue-specific contributions to RCT are still not well defined.

Approach and Results—

Using tissue-specific LXR deletions together with in vitro and in vivo assays of cholesterol efflux and fecal cholesterol excretion, we demonstrate that macrophage LXR activity is neither necessary nor sufficient for LXR agonist–stimulated RCT. In contrast, the ability of LXR agonists primarily acting in the intestine to increase HDL mass and HDL function seems to underlie the ability of LXR agonists to stimulate RCT in vivo.

Conclusions—

We demonstrate that activation of LXR in macrophages makes little or no contribution to LXR agonist–stimulated RCT. Unexpectedly, our studies suggest that the ability of macrophages to efflux cholesterol to HDL in vivo is not regulated by macrophage activity but is primarily determined by the quantity and functional activity of HDL.
Sequencing of
SCN5A
Identifies Rare and Common Variants Associated With Cardiac Conduction: Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium
Authors: Magnani Jared W. , Brody Jennifer A. , Prins Bram P. , Arking Dan E. , Lin Honghuang , Yin Xiaoyan , Liu Ching-Ti , Morrison Alanna C. , Zhang Feng , Spector Tim D. , Alonso Alvaro , Bis Joshua C. , Heckbert Susan R. , Lumley Thomas , Sitlani Colleen M. , Cupples L. Adrienne , Lubitz Steven A. , Soliman Elsayed Z. , Pulit Sara L. , Newton-Cheh Christopher , O’Donnell Christopher J. , Ellinor Patrick T. , Benjamin Emelia J. , Muzny Donna M. , Gibbs Richard A. , Santibanez Jireh , Taylor Herman A. , Rotter Jerome I. , Lange Leslie A. , Psaty Bruce M. , Jackson Rebecca , Rich Stephen S. , Boerwinkle Eric , Jamshidi Yalda , Sotoodehnia Nona
Published: June 2014

Background—

The cardiac sodium channel
SCN5A
regulates atrioventricular and ventricular conduction. Genetic variants in this gene are associated with PR and QRS intervals. We sought to characterize further the contribution of rare and common coding variation in
SCN5A
to cardiac conduction.

Methods and Results—

In Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium Targeted Sequencing Study, we performed targeted exonic sequencing of
SCN5A
(n=3699, European ancestry individuals) and identified 4 common (minor allele frequency >1%) and 157 rare variants. Common and rare SCN5A coding variants were examined for association with PR and QRS intervals through meta-analysis of European ancestry participants from CHARGE, National Heart, Lung, and Blood Institute’s Exome Sequencing Project (n=607), and the UK10K (n=1275) and by examining Exome Sequencing Project African ancestry participants (n=972). Rare coding
SCN5A
variants in aggregate were associated with PR interval in European and African ancestry participants (
P
=1.3×10
−3
). Three common variants were associated with PR and QRS interval duration among European ancestry participants and one among African ancestry participants. These included 2 well-known missense variants: rs1805124 (H558R) was associated with PR and QRS shortening in European ancestry participants (
P
=6.25×10
−4
and
P
=5.2×10
−3
, respectively) and rs7626962 (S1102Y) was associated with PR shortening in those of African ancestry (
P
=2.82×10
−3
). Among European ancestry participants, 2 novel synonymous variants, rs1805126 and rs6599230, were associated with cardiac conduction. Our top signal, rs1805126 was associated with PR and QRS lengthening (
P
=3.35×10
−7
and
P
=2.69×10
−4
, respectively) and rs6599230 was associated with PR shortening (
P
=2.67×10
−5
).

Conclusions—

By sequencing
SCN5A
, we identified novel common and rare coding variants associated with cardiac conduction.
Strategies to Design and Analyze Targeted Sequencing Data
Authors: Lin Honghuang , Wang Min , Brody Jennifer A. , Bis Joshua C. , Dupuis Josée , Lumley Thomas , McKnight Barbara , Rice Kenneth M. , Sitlani Colleen M. , Reid Jeffrey G. , Bressler Jan , Liu Xiaoming , Davis Brian C. , Johnson Andrew D. , O’Donnell Christopher J. , Kovar Christie L. , Dinh Huyen , Wu Yuanqing , Newsham Irene , Chen Han , Broka Andi , DeStefano Anita L. , Gupta Mayetri , Lunetta Kathryn L. , Liu Ching-Ti , White Charles C. , Xing Chuanhua , Zhou Yanhua , Benjamin Emelia J. , Schnabel Renate B. , Heckbert Susan R. , Psaty Bruce M. , Muzny Donna M. , Cupples L. Adrienne , Morrison Alanna C. , Boerwinkle Eric
Published: June 2014

Background—

Genome-wide association studies have identified thousands of genetic variants that influence a variety of diseases and health-related quantitative traits. However, the causal variants underlying the majority of genetic associations remain unknown. Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium Targeted Sequencing Study aims to follow up genome-wide association study signals and identify novel associations of the allelic spectrum of identified variants with cardiovascular-related traits.

Methods and Results—

The study included 4231 participants from 3 CHARGE cohorts: the Atherosclerosis Risk in Communities Study, the Cardiovascular Health Study, and the Framingham Heart Study. We used a case–cohort design in which we selected both a random sample of participants and participants with extreme phenotypes for each of 14 traits. We sequenced and analyzed 77 genomic loci, which had previously been associated with ≥1 of 14 phenotypes. A total of 52 736 variants were characterized by sequencing and passed our stringent quality control criteria. For common variants (minor allele frequency ≥1%), we performed unweighted regression analyses to obtain
P
values for associations and weighted regression analyses to obtain effect estimates that accounted for the sampling design. For rare variants, we applied 2 approaches: collapsed aggregate statistics and joint analysis of variants using the sequence kernel association test.

Conclusions—

We sequenced 77 genomic loci in participants from 3 cohorts. We established a set of filters to identify high-quality variants and implemented statistical and bioinformatics strategies to analyze the sequence data and identify potentially functional variants within genome-wide association study loci.
Inflammation and Immunity in the Pathogenesis of Pulmonary Arterial Hypertension
Authors: Rabinovitch Marlene , Guignabert Christophe , Humbert Marc , Nicolls Mark R.
Published: June 2014

This review summarizes an expanding body of knowledge indicating that failure to resolve inflammation and altered immune processes underlie the development of pulmonary arterial hypertension. The chemokines and cytokines implicated in pulmonary arterial hypertension that could form a biomarker platform are discussed. Pre-clinical studies that provide the basis for dysregulated immunity in animal models of the disease are reviewed. In addition, we present therapies that target inflammatory/immune mechanisms that are currently enrolling patients, and discuss others in development. We show how genetic and metabolic abnormalities are inextricably linked to dysregulated immunity and adverse remodeling in the pulmonary arteries.
Symptomatic Presentation of Carotid Sinus Hypersensitivity Is Associated With Impaired Cerebral Autoregulation
Authors: Tan Maw Pin , Chadwick Tom J. , Kerr Simon R. J. , Parry Steve W.
Published: June 2014

Background

Carotid sinus hypersensitivity (
CSH
) is associated with syncope, unexplained falls, and drop attacks in older people but occurs asymptomatically in 35% of community‐dwelling elders. We hypothesized that impaired cerebral autoregulation is associated with the conversion of asymptomatic
CSH
to symptomatic
CSH
. We therefore conducted a case–control study evaluating individuals with
CSH
with and without the symptoms of syncope or unexplained falls, as well as non‐
CSH
controls, to determine whether the blood pressure and heart rate changes associated with
CSH
are associated with symptoms only when cerebral autoregulation is altered.

Methods and Results

Bilateral middle cerebral artery blood flow velocities (
BFV
) were measured in consecutive patients with symptomatic
CSH
(n=22) and asymptomatic controls with (n=18) and without
CSH
(n=14) using transcranial Doppler ultrasonography during lower body negative pressure‐induced systemic hypotension. Within‐group comparisons revealed significantly lower cerebrovascular resistance index (
CVR
i
) at nadir for the asymptomatic
CSH
group (right, mean [95%
CI
]: 2.2 [1.8, 2.8] versus 2.6 [2.2, 3.0];
P
=0.005; left: 2.8 [2.4, 3.3] versus 3.1 [2.7, 3.8];
P
=0.016). Between‐group comparisons showed higher mean
BFV
(right: estimated mean difference, B=5.49 [1.98, 8.80],
P
=0.003; left: 4.82 [1.52, 8.11],
P
=0.005) and lower
CVR
i
(right: B=0.08 [0.03, 0.12],
P
=0.003, left: B=0.07 [0.02, 0.12],
P
=0.006) in asymptomatic
CSH
versus symptomatic
CSH
groups. There were no significant differences in bilateral mean
BFV
or right
CVR
i
between the non‐
CSH
and symptomatic
CSH
groups but differences were present for left
CVR
i
(B=0.07 [0.02, 0.013],
P
=0.015).

Conclusion

Cerebral autoregulation is altered in symptomatic
CSH
and therefore appears to be associated with the development of hypotension‐related symptoms in individuals with
CSH
.
DNA Methylation is Developmentally Regulated for Genes Essential for Cardiogenesis
Authors: Chamberlain Alyssa A. , Lin Mingyan , Lister Rolanda L. , Maslov Alex A. , Wang Yidong , Suzuki Masako , Wu Bingruo , Greally John M. , Zheng Deyou , Zhou Bin
Published: June 2014

Background

DNA
methylation is a major epigenetic mechanism altering gene expression in development and disease. However, its role in the regulation of gene expression during heart development is incompletely understood. The aim of this study is to reveal
DNA
methylation in mouse embryonic hearts and its role in regulating gene expression during heart development.

Methods and Results

We performed the genome‐wide
DNA
methylation profiling of mouse embryonic hearts using methyl‐sensitive, tiny fragment enrichment/massively parallel sequencing to determine methylation levels at
ACGT
sites. The results showed that while global methylation of 1.64 million
ACGT
sites in developing hearts remains stable between embryonic day (E) 11.5 and E14.5, a small fraction (2901) of them exhibit differential methylation. Gene Ontology analysis revealed that these sites are enriched at genes involved in heart development. Quantitative real‐time
PCR
analysis of 350 genes with differential
DNA
methylation showed that the expression of 181 genes is developmentally regulated, and 79 genes have correlative changes between methylation and expression, including hyaluronan synthase 2 (
Has2
). Required for heart valve formation,
Has2
expression in the developing heart valves is downregulated at E14.5, accompanied with increased
DNA
methylation in its enhancer. Genetic knockout further showed that the downregulation of
Has2
expression is dependent on
DNA
methyltransferase 3b, which is co‐expressed with
Has2
in the forming heart valve region, indicating that the
DNA
methylation change may contribute to the
Has2
enhancer's regulating function.

Conclusions

DNA
methylation is developmentally regulated for genes essential to heart development, and abnormal
DNA
methylation may contribute to congenital heart disease.