bluuebunny/crossref_metadata_2025 huggingface dataset:
Comparison Among Different High Porosity Stent Configurations: Hemodynamic Effects of Treatment in a Large Cerebral Aneurysm
Authors: Roszelle Breigh N. , Nair Priya , Gonzalez L. Fernando , Haithem Babiker M. , Ryan Justin , Frakes David
Published: December 2013

Whether treated surgically or with endovascular techniques, large and giant cerebral aneurysms are particularly difficult to treat. Nevertheless, high porosity stents can be used to accomplish stent-assisted coiling and even standalone stent-based treatments that have been shown to improve the occlusion of such aneurysms. Further, stent assisted coiling can reduce the incidence of complications that sometimes result from embolic coiling (e.g., neck remnants and thromboembolism). However, in treating cerebral aneurysms at bifurcation termini, it remains unclear which configuration of high porosity stents will result in the most advantageous hemodynamic environment. The goal of this study was to compare how three different stent configurations affected fluid dynamics in a large patient-specific aneurysm model. Three common stent configurations were deployed into the model: a half-Y, a full-Y, and a crossbar configuration. Particle image velocimetry was used to examine post-treatment flow patterns and quantify root-mean-squared velocity magnitude (VRMS) within the aneurysmal sac. While each configuration did reduce VRMS within the aneurysm, the full-Y configuration resulted in the greatest reduction across all flow conditions (an average of 56% with respect to the untreated case). The experimental results agreed well with clinical follow up after treatment with the full-Y configuration; there was evidence of thrombosis within the sac from the stents alone before coil embolization was performed. A computational simulation of the full-Y configuration aligned well with the experimental and in vivo findings, indicating potential for clinically useful prediction of post-treatment hemodynamics. This study found that applying different stent configurations resulted in considerably different fluid dynamics in an anatomically accurate aneurysm model and that the full-Y configuration performed best. The study indicates that knowledge of how stent configurations will affect post-treatment hemodynamics could be important in interventional planning and demonstrates the capability for such planning based on novel computational tools.
Ultrafast Long-Range Charge Separation in Organic Semiconductor Photovoltaic Diodes
Authors: Gélinas Simon , Rao Akshay , Kumar Abhishek , Smith Samuel L. , Chin Alex W. , Clark Jenny , van der Poll Tom S. , Bazan Guillermo C. , Friend Richard H.
Published: December 2013

Early Separation

In photovoltaic devices, electrons excited by the absorption of light must travel across a junction, while the positively charged “holes” they leave behind effectively migrate in the opposite direction. If the electrons and holes do not separate efficiently, they can recombine and fail to produce any appreciable current.

Gélinas
et al.

(p.
512
, published online 12 December; see the Perspective by

Bredas

) studied this separation process by ultrafast optical absorption spectroscopy in thiophene-derived donor-fullerene acceptor systems common in organic photovoltaics and report a rate significantly faster than simple charge diffusion would suggest. The results implicate a coherent charge delocalization process, likely to involve fullerene π-electron states.
Genetic Screens in Human Cells Using the CRISPR-Cas9 System
Authors: Wang Tim , Wei Jenny J. , Sabatini David M. , Lander Eric S.
Published: December 2013

Improving Whole-Genome Screens

Improved methods are needed for the knockout of individual genes in genome-scale functional screens.

Wang
et al.

(p.
80
, published online 12 December) and

Shalem
et al.

(p.
84
, published online 12 December) used the bacterial CRISPR/Cas9 system to power-screen protocols that avoid several of the pitfalls associated with small interfering RNA (siRNA) screens. Genome editing by these methods completely disrupts target genes, thus avoiding weak signals that can occur when transcript abundance is partially decreased by siRNA. Furthermore, gene targeting by the CRISPR system is more precise and appears to produce substantially fewer off-target effects than existing methods.
Draft Genome Sequence of “
Candidatus
Halobonum tyrrellensis” Strain G22, Isolated from the Hypersaline Waters of Lake Tyrrell, Australia
Authors: Ugalde Juan A. , Narasingarao Priya , Kuo Sidney , Podell Sheila , Allen Eric E.
Published: December 2013

We report the draft 3.675-Mbp genome sequence of “
Candidatus
Halobonum tyrrellensis” strain G22, a novel halophilic archaeon isolated from the surface hypersaline waters of Lake Tyrrell, Australia. The availability of the first genome from the “
Candidatus
Halobonum” genus provides a new genomic resource for the comparative genomic analysis of halophilic
Archaea
.
Complete Genome Sequence of Porcine Encephalomyocarditis Virus Strain BD2
Authors: Yuan Wanzhe , Zhang Xiuyuan , Sun Jiguo
Published: December 2013

Encephalomyocarditis virus (EMCV) causes acute myocarditis in young pigs or reproductive failure in sows, and it is divided into two main groups. Here, we report the complete genome sequence of EMCV strain BD2, which belongs to group I.
High-Quality Draft Genome Sequences of Xanthomonas axonopodis pv. glycines Strains CFBP 2526 and CFBP 7119
Authors: Darrasse A. , Bolot S. , Serres-Giardi L. , Charbit E. , Boureau T. , Fisher-Le Saux M. , Briand M. , Arlat M. , Gagnevin L. , Koebnik R. , Noël L. D. , Carrère S. , Jacques M. A.
Published: December 2013

We report here the high-quality draft genome sequences of two strains of
Xanthomonas axonopodis
pv. glycines, the causal agent of bacterial pustule on soybeans. Comparison of these genomes with those of phylogenetically closely related pathovars of
Xanthomonas
spp. will help to understand the mechanisms involved in host specificity and adaptation to host plants.
Draft Genome Sequence of Staphylococcus simulans UMC-CNS-990, Isolated from a Case of Chronic Bovine Mastitis
Authors: Calcutt Michael J. , Foecking Mark F. , Hsieh Hsin-Yeh , Perry Jeanette , Stewart George C. , Middleton John R.
Published: December 2013

Coagulase-negative staphylococci are frequently isolated from cases of subclinical bovine mastitis. Reported here is a draft genome sequence of
Staphylococcus simulans
UMC-CNS-990, an isolate recovered from a chronic intramammary infection of a Holstein cow. Unexpectedly, a cluster of genes encoding gas vesicle proteins was found within the 2,755-kb genome.
Draft Genome Sequence of Fusobacterium nucleatum subsp.
vincentii
ChDC F8, Isolated from a Human Subgingival Plaque in the Republic of Korea
Authors: Park Soon-Nang , Cho Eugene , Kim Hwa-Sook , Kim Dae-Soo , Jung Jaeeun , Baek Jeong-Hun , Kyong Lim Yun , Jo Eojin , Chang Young-Hyo , Hwan Shin Jeong , Kim Jihun , Choi Sang-Haeng , Kang Jihee , Choi YongUn , Park Hong-Seog , Kim Hongik , Kook Joong-Ki
Published: December 2013

Fusobacterium nucleatum
is a Gram-negative, nonmotile, obligately anaerobic rod bacterium which might play an important role in the initiation and progression of periodontal diseases.
F. nucleatum
subsp.
vincentii
ChDC F8 (KCOM 1231) was isolated from a human gingivitis lesion. Here, we report the draft genome sequence of the strain.
Full
-
Genome Sequence of Hibiscus Chlorotic Ringspot Virus from Israel
Authors: Luria Neta , Reingold Victoria , Lachman Oded , Dombrovsky Aviv
Published: December 2013

Hibiscus rosa-sinensis
is one of the most prevalent ornamental plants grown in private and public gardens. Hibiscus chlorotic ringspot virus (HCRSV) is a member of the
Carmovirus
genus, with a positive single-strand RNA that putatively encodes seven proteins. The complete genome of the first Israeli isolate of HCRSV, HCRSV-IL, comprises 3,908 nucleotides and shows 93% nucleotide sequence identity to the Singapore isolate and 87% identity to the Taiwanese isolate.
Unilateral visual loss after spine surgery in the prone position for extradural haematoma in a healthy young man
Authors: Ooi Edwin Inn Loon , Ahem Amin , Zahidin Aida Zairani , Bastion Mae-Lynn Catherine
Published: December 2013

This case reports a patient who developed central retinal artery occlusion following spinal surgery in the prone position. When placed in this position, especially as a result of malposition of the head, the patient may develop external compression of the eye which leads to central retinal artery occlusion. Therefore, a special precaution must be given for adequate eye protection during prolonged prone-positioned spine surgery.
Unilateral brain oedema related to focal status epilepticus
Authors: Ali Noura Abdulwahid , Palat Chirakkara Sudhir Kumar , Reddy Jagan Jinna , Sinha Shobhit
Published: December 2013

We present a female patient in her late 30s, with baseline vegetative state following prior traumatic brain injury, who presented with prolonged right hemispheric status epilepticus. The neuroimaging revealed a striking right-sided pancortical oedema with left (crossed) cerebellar diaschisis and dilation of right hemispheric arteries. EEG was concordant and showed nearly continuous right hemispheric seizure discharges with suppressed background. Infective and vascular aetiologies were ruled out. The patient showed clinical and electrographic improvement following treatment with antiepileptic drugs. Unilateral cerebral oedema is a rare presentation of focal status epilepticus, and should be considered as a differential diagnosis in the appropriate clinical scenario.
Effect of increased fire activity on global warming in the boreal forest
Authors: Oris France , Asselin Hugo , Ali Adam A. , Finsinger Walter , Bergeron Yves
Published: December 2013

Forest fires are an important disturbance in the boreal forest. They are influenced by climate, weather, topography, vegetation, surface deposits, and human activities. In return, forest fires affect the climate through emission of gases and aerosols, and changes in surface albedo, soil processes, and vegetation dynamics. The net effect of these factors is not yet well established but seems to have caused a negative feedback on climate during the 20th century. However, an increase in boreal forest fires is predicted by the end of the 21st century, possibly changing the effect of fires on climate change to a positive feedback that would exacerbate global warming. This review presents (1) an overview of fire regimes and vegetation succession in boreal forests; (2) the effects on climate of combustion emissions and post-fire changes in ecosystem functioning; (3) the effects of fire regime variations on climate, especially on carbon stock and surface albedo; (4) an integrative approach of fire effects on climate dynamics; and (5) the implications of increased fire activity on global warming by calculating the radiative forcing of several factors by 2100 in the boreal region, before discussing the results and exposing the limits of the data at hand. Generally, losses of carbon from forest fires in the boreal region will increase in the future and their effect on the carbon stock (0.37 W/m2/decade) will be greater than the effect of fire on surface albedo (−0.09 W/m2/decade). The net effect of aerosol emissions from boreal fires will likely cause a positive feedback on global warming. This review emphasizes the importance of feedbacks between fires and climate in the boreal forest. It presents limitations and uncertainties to be addressed in future studies, particularly with regards to the effect of CO2 fertilization on forest productivity, which could offset or mitigate the effect of fire.
Curvature properties of Gödel metric
Authors: Deszcz Ryszard , Hotloś Marian , Jełowicki Jan , Kundu Haradhan , Shaikh Absos Ali
Published: December 2013

The main aim of this paper is to investigate the geometric structures admitting by the Gödel spacetime which produces a new class of semi-Riemannian manifolds. We also consider some extension of Gödel metric.
Detrital zircon U–Pb and
40
Ar/
39
Ar hornblende ages from the Aileu Complex, Timor-Leste: provenance and metamorphic cooling history
Authors: Ely Kim S. , Sandiford Mike , Phillips David , Boger Steven D.
Published: December 2013

Geochronological data from the Aileu Complex provide new constraints on the development of the Banda Arc–continent collision. Detrital zircons of the Aileu Complex have major U–Pb age modes at 270–440 Ma, 860–1240 Ma and 1460–1870 Ma, most compatible with a sediment source located in SE Asia as part of the now fragmented Sula Spur.
40
Ar/
39
Ar cooling ages of hornblende demonstrate an extended cooling history across the complex, with the eastern parts cooling through hornblende closure temperature by 10 Ma and central parts by 6 Ma, consistent with a variable exhumation history. The onset of cooling by 10 Ma implies that metamorphism was probably coeval with initiation of the Banda Arc. We propose that the Aileu Complex cooling ages record deformation related to fragmentation of the Sula Spur and early development of the Banda Arc, rather than collision between the Australian continent and the Banda Arc.

Supplementary material:

Detrital zircon U–Pb analytical results, hornblende argon isotope geochronology sample details, hornblende
40
Ar/
39
Ar step heating analytical results and hornblende electron microprobe analytical results are available at
www.geolsoc.org.uk/SUP18702
.
Push-up inversion structures v. fault-bend reactivation anticlines along oblique thrust ramps: examples from the Apennines fold-and-thrust belt (Italy)
Authors: Pace P. , Calamita F.
Published: December 2013

The study of inversion structures in fold-and-thrust belts that originated as extensional faults is valuable for the development of geometric and kinematic models that are helpful in unravelling the structural style and for detecting structural hydrocarbon traps. We document push-up inversion structures versus fault-bend reactivation anticlines occurring along oblique thrust ramps, by examining examples of buried Apulian structures in the Central–Southern Apennines and outcropping thrust-related folds in the Central–Northern Apennines of Italy. The different geometric features between push-up inversion structures and fault-bend reactivation anticlines are functionally controlled by the mechanical characteristics of the involved sedimentary multilayer, the original architecture of the former extensional basin, and the amount of thrust displacement. The recognition of such inversion structures is important in understanding the anatomy and structural style of foreland fold-and-thrust belts. In addition, their identification is critical in interpreting the geometry and types of structural traps that may be expected along oblique thrust ramps. This study reveals that push-up inversion structures and fault-bend reactivation anticlines could coexist along oblique thrust ramps within a curved thrust system and may be detected among analogous foreland thrust belts that include inherited extensional basins.
Functional consequences ofEpCammutation in mice and men
Authors: Mueller James L. , McGeough Matthew D. , Peña Carla A. , Sivagnanam Mamata
Published: December 2013

Congenital tufting enteropathy (CTE) is a severe diarrheal disease of infancy characterized by villous changes and epithelial tufts. We previously identified mutations in epithelial cell adhesion molecule ( EpCAM) as the cause of CTE. We developed an in vivo mouse model of CTE based on EpCAM mutations found in patients with the aim to further elucidate the in vivo role of EpCAM and allow for a direct comparison to human CTE. Using Cre-LoxP recombination technology, we generated a construct lacking exon 4 in Epcam. EpcamΔ4/Δ4mice and CTE patient intestinal tissue integrity was analyzed by histology using both light immunohistochemistry and electron microscopy. EpcamΔ4/Δ4mice demonstrate neonatal lethality and growth retardation with pathological features, including epithelial tufts, enterocyte crowding, altered desmosomes, and intercellular gaps, similar to human CTE patients. Mutant EpCAM protein is present at low levels and is mislocalized in the intestine of EpcamΔ4/Δ4mice and CTE patients. Deletion of exon 4 was found to decrease expression of both EpCAM and claudin-7 causing a loss of colocalization, functionally disrupting the EpCAM/claudin-7 complex, a finding for the first time confirmed in CTE patients. Furthermore, compared with unaffected mice, mutation of Epcam leads to enhanced permeability and intestinal cell migration, uncovering underlying disease mechanisms.
Timing of return from altitude training for optimal sea level performance
Authors: Chapman Robert F. , Laymon Stickford Abigail S. , Lundby Carsten , Levine Benjamin D.
Published: December 2013

While a number of published studies exist to guide endurance athletes with the best practices regarding implementation of altitude training, a key unanswered question concerns the proper timing of return to sea level prior to major competitions. Evidence reviewed here suggests that, altogether, the deacclimatization responses of hematological, ventilatory, and biomechanical factors with return to sea level likely interact to determine the best timing for competitive performance.
Dietary nitrate facilitates an acetazolamide-induced increase in cerebral blood flow during visual stimulation
Authors: Aamand Rasmus , Ho Yi-Ching Lynn , Dalsgaard Thomas , Roepstorff Andreas , Lund Torben E.
Published: December 2013

The carbonic anhydrase (CA) inhibitor acetazolamide (AZ) is used routinely to estimate cerebrovascular reserve capacity in patients, as it reliably increases cerebral blood flow (CBF). However, the mechanism by which AZ accomplishes this CBF increase is not entirely understood. We recently discovered that CA can produce nitric oxide (NO) from nitrite, and that AZ enhances this NO production in vitro. In fact, this interaction between AZ and CA accounted for a large part of AZ's vasodilatory action, which fits well with the known vasodilatory potency of NO. The present study aimed to assess whether AZ acts similarly in vivo in the human cerebrovascular system. Hence, we increased or minimized the dietary intake of nitrate in 20 healthy male participants, showed them a full-field flickering dartboard, and measured their CBF response to this visual stimulus with arterial spin labeling. Doing so, we found a significant positive interaction between the dietary intake of nitrate and the CBF modulation afforded by AZ during visual stimulation. In addition, but contrary to studies conducted in elderly participants, we report no effect of nitrate intake on resting CBF in healthy human participants. The present study provides in vivo support for an enhancing effect of AZ on the NO production from nitrite catalyzed by CA in the cerebrovascular system. Furthermore, our results, in combination with the results of other groups, indicate that nitrate may have significant importance to vascular function when the cerebrovascular system is challenged by age or disease.
Ventilatory long-term facilitation is evident after initial and repeated exposure to intermittent hypoxia in mice genetically depleted of brain serotonin
Authors: Hickner Stephen , Hussain Najaah , Angoa-Perez Mariana , Francescutti Dina M. , Kuhn Donald M. , Mateika Jason H.
Published: December 2013

Our study was designed to determine if central nervous system (CNS) serotonin is required for the induction of ventilatory long-term facilitation (LTF) in intact, spontaneously breathing mice. Nineteen tryptophan hydroxylase 2-deficient (Tph2−/−) mice, devoid of serotonin in the CNS, and their wild-type counterparts (Tph2+/+) were exposed to intermittent hypoxia each day for 10 consecutive days. The ventilatory response to intermittent hypoxia was greater in the Tph2+/+compared with the Tph2−/−mice (1.10 ± 0.10 vs. 0.77 ± 0.01 ml min−1·percent−1oxygen; P ≤ 0.04). Ventilatory LTF, caused by increases in breathing frequency, was evident in Tph2+/+and Tph2−/−mice following exposure to intermittent hypoxia each day; however, the magnitude of the response was greater in the Tph2+/+compared with the Tph2−/−mice (1.11 ± 0.02 vs. 1.05 ± 0.01 normalized to baseline on each day; P ≤ 0.01). The magnitude of ventilatory LTF increased significantly from the initial to the finals days of the protocol in the Tph2−/−(1.06 ± 0.02 vs. 1.11 ± 0.03 normalized to baseline on the initial days; P ≤ 0.004) but not in the Tph2+/+mice. This enhanced response was mediated by increases in tidal volume. Body temperature and metabolic rate did not account for differences in the magnitude of ventilatory LTF observed between groups after acute and repeated daily exposure to intermittent hypoxia. We conclude that ventilatory LTF, after acute exposure to intermittent hypoxia, is mediated by increases in breathing frequency and occurs in the absence of serotonin, although the magnitude of the response is diminished. This weakened response is enhanced following repeated daily exposure to intermittent hypoxia, via increases in tidal volume, to a similar magnitude evident in Tph2+/+mice. Thus the magnitude of ventilatory LTF following repeated daily exposure to intermittent hypoxia is not dependent on the presence of CNS serotonin.
The CXCL7/CXCR1/2 Axis Is a Key Driver in the Growth of Clear Cell Renal Cell Carcinoma
Authors: Grépin Renaud , Guyot Mélanie , Giuliano Sandy , Boncompagni Marina , Ambrosetti Damien , Chamorey Emmanuel , Scoazec Jean-Yves , Negrier Sylvie , Simonnet Hélène , Pagès Gilles
Published: December 2013

Mutations in the von Hippel–Lindau gene upregulate expression of the central angiogenic factor VEGF, which drives abnormal angiogenesis in clear cell renal cell carcinomas (ccRCC). However, the overexpression of VEGF in these tumors was not found to correlate with overall survival. Here, we show that the proangiogenic, proinflammatory cytokine CXCL7 is an independent prognostic factor for overall survival in this setting. CXCL7 antibodies strongly reduced the growth of ccRCC tumors in nude mice. Conversely, conditional overexpression of CXCL7 accelerated ccRCC development. CXCL7 promoted cell proliferation in vivo and in vitro, in which expression of CXCL7 was induced by the central proinflammatory cytokine interleukin (IL)-1β. ccRCC cells normally secrete low amounts of CXCL7; it was more highly expressed in tumors due to high levels of IL-1β there. We found that a pharmacological inhibitor of the CXCL7 receptors CXCR1 and CXCR2 (SB225002) was sufficient to inhibit endothelial cell proliferation and ccRCC growth. Because CXCR1 and CXCR2 are present on both endothelial and ccRCC cells, their inhibition affected both the tumor vasculature and the proliferation of tumor cells. Our results highlight the CXCL7/CXCR1/CXCR2 axis as a pertinent target for the treatment of ccRCC. Cancer Res; 74(3); 873–83. ©2013 AACR.
Histone Chaperone CHAF1A Inhibits Differentiation and Promotes Aggressive Neuroblastoma
Authors: Barbieri Eveline , De Preter Katleen , Capasso Mario , Chen Zaowen , Hsu Danielle M. , Tonini Gian Paolo , Lefever Steve , Hicks John , Versteeg Rogier , Pession Andrea , Speleman Frank , Kim Eugene S. , Shohet Jason M.
Published: December 2013

Neuroblastoma arises from the embryonal neural crest secondary to a block in differentiation. Long-term patient survival correlates inversely with the extent of differentiation, and treatment with retinoic acid or other prodifferentiation agents improves survival modestly. In this study, we show the histone chaperone and epigenetic regulator CHAF1A functions in maintaining the highly dedifferentiated state of this aggressive malignancy. CHAF1A is a subunit of the chromatin modifier chromatin assembly factor 1 and it regulates H3K9 trimethylation of key target genes regulating proliferation, survival, and differentiation. Elevated CHAF1A expression strongly correlated with poor prognosis. Conversely, CHAF1A loss-of-function was sufficient to drive neuronal differentiation in vitro and in vivo. Transcriptome analysis of cells lacking CHAF1A revealed repression of oncogenic signaling pathways and a normalization of glycolytic metabolism. Our findings demonstrate that CHAF1A restricts neural crest differentiation and contributes to the pathogenesis of high-risk neuroblastoma. Cancer Res; 74(3); 765–74. ©2013 AACR.
Targeting Akt3 Signaling in Triple-Negative Breast Cancer
Authors: Chin Y. Rebecca , Yoshida Taku , Marusyk Andriy , Beck Andrew H. , Polyak Kornelia , Toker Alex
Published: December 2013

Triple-negative breast cancer (TNBC) is currently the only major breast tumor subtype without effective targeted therapy and, as a consequence, in general has a poor outcome. To identify new therapeutic targets in TNBC, we performed a short hairpin RNA (shRNA) screen for protein kinases commonly amplified and overexpressed in breast cancer. Using this approach, we identified AKT3 as a gene preferentially required for the growth of TNBCs. Downregulation of Akt3 significantly inhibits the growth of TNBC lines in three-dimensional (3D) spheroid cultures and in mouse xenograft models, whereas loss of Akt1 or Akt2 have more modest effects. Akt3 silencing markedly upregulates the p27 cell-cycle inhibitor and this is critical for the ability of Akt3 to inhibit spheroid growth. In contrast with Akt1, Akt3 silencing results in only a minor enhancement of migration and does not promote invasion. Depletion of Akt3 in TNBC sensitizes cells to the pan-Akt inhibitor GSK690693. These results imply that Akt3 has a specific function in TNBCs; thus, its therapeutic targeting may provide a new treatment option for this tumor subtype. Cancer Res; 74(3); 964–73. ©2013 AACR.
Inhibition of Insulin-like Growth Factor–Binding Protein-3 Signaling through Sphingosine Kinase-1 Sensitizes Triple-Negative Breast Cancer Cells to EGF Receptor Blockade
Authors: Martin Janet L. , de Silva Hasanthi C. , Lin Mike Z. , Scott Carolyn D. , Baxter Robert C.
Published: December 2013

The type I EGF receptor (EGFR or ErbB1) and insulin-like growth factor–binding protein-3 (IGFBP-3) are highly expressed in triple-negative breast cancer (TNBC), a particularly aggressive disease that cannot be treated with conventional therapies targeting the estrogen or progesterone receptors (ER and PR), or HER2. We have shown previously in normal breast epithelial cells that IGFBP-3 potentiates growth-stimulatory signaling transduced by EGFR, and this is mediated by the sphingosine kinase-1 (SphK1)/sphingosine 1-phosphate (S1P) system. In this study, we investigated whether cotargeting the EGFR and SphK1/S1P pathways in TNBC cells results in greater growth inhibition compared with blocking either alone, and might therefore have novel therapeutic potential in TNBC. In four TNBC cell lines, exogenous IGFBP-3 enhanced ligand-stimulated EGFR activation, associated with increased SphK1 localization to the plasma membrane. The effect of exogenous IGFBP-3 on EGFR activation was blocked by pharmacologic inhibition or siRNA-mediated silencing of SphK1, and silencing of endogenous IGFBP-3 also suppressed EGF-stimulated EGFR activation. Real-time analysis of cell proliferation revealed a combined effect of EGFR inhibition by gefitinib and SphK1 inhibition using SKi-II. Growth of MDA-MB-468 xenograft tumors in mice was significantly inhibited by SKi-II and gefitinib when used in combination, but not as single agents. We conclude that IGFBP-3 promotes growth of TNBC cells by increasing EGFR signaling, that this is mediated by SphK1, and that combined inhibition of EGFR and SphK1 has potential as an anticancer therapy in TNBC in which EGFR and IGFBP-3 expression is high. Mol Cancer Ther; 13(2); 316–28. ©2013 AACR.
PP6C Hotspot Mutations in Melanoma Display Sensitivity to Aurora Kinase Inhibition
Authors: Gold Heidi L. , Wengrod Jordan , de Miera Eleazar Vega-Saenz , Wang Ding , Fleming Nathaniel , Sikkema Lisa , Kirchhoff Tomas , Hochman Tsivia , Goldberg Judith D. , Osman Iman , Gardner Lawrence B.
Published: December 2013

Recent whole genome melanoma sequencing studies have identified recurrent mutations in the gene encoding the catalytic subunit of serine/threonine phosphatase 6 (PPP6C/PP6C). However, the biochemical, functional, and clinical ramifications of these mutations are unknown. Sequencing PP6C from patients with melanoma (233 primary and 77 metastatic specimens) with extended prospective clinical outcome revealed a large number of hotspot mutations in patients with both primary and metastatic melanoma. Despite minimal association between stage and presence of PP6C mutations in patients with primary melanoma, a subpopulation of cells within each tumor did contain PP6C mutations, suggesting PP6C mutation is an early, but non–tumor-initiating event in melanoma. Among patients with primary melanoma with PP6C mutations, patients with stop mutations had significantly shorter recurrence-free survival compared with patients without stop mutations. In addition, PP6C mutations were independent of commonly observed BRAF and NRAS mutations. Biochemically, PP6C mutations could be classified as those that interact with PP6C regulatory subunits and those that do not. Mutations that did not bind to PP6C regulatory subunits were associated with increased phosphorylation of Aurora kinase, a PP6C substrate, and mitotic defects. However, both classes of PP6C mutations led to increased sensitivity to Aurora kinase inhibition. Together, these data support for the first time that PP6C mutations are molecularly, biochemically, and clinically heterogeneous.

Implications: PP6C mutations have distinct functional and clinical consequences in melanoma, and confer sensitivity to Aurora A kinase inhibitors. Mol Cancer Res; 12(3); 433–9. ©2013 AACR.
Limited Positron Emission Tomography-Computed Tomography for Restaging of Lymphoma: A Strategy for Reducing Radiation Exposure among Patients with Early-Stage Curable Lymphoma
Authors: Wolach Ofir , Bernstine Hanna , Edel Yonatan , Bairey Osnat , Shpilberg Ofer , Groshar David , Lahav Meir
Published: December 2013

Repeated imaging with positron emission tomography-computed tomography (PET-CT) is associated with cumulative exposure to substantial doses of radiation. Furthermore, PET-CT is an expensive and limited resource in many institutions. We conducted a retrospective analysis to evaluate whether limited PET-CT focused on the initially involved field of view (FOV) at diagnosis, corresponding to an above- or below-the-diaphragm scan, is sufficient for follow-up of patients with Hodgkin (HL) and aggressive non-Hodgkin lymphoma (NHL). One hundred thirty-one examinations of 44 patients with early-stage (I-II) HL (n = 27) and aggressive NHL (n = 17) who had PET-CT performed as part of their initial staging and at follow-up were analyzed. Regardless of the extent of response to treatment, there was no single case in which the disease progressed outside of the initially involved FOV (0/44, 95% CI 0-0.08). This was true even in cases of disease progression, including in the setting of relapse. Our findings suggest that limited PET-CT analysis of the initially involved FOV in patients with early-stage curable lymphoma may be satisfactory for response assessment.
Induction of Apoptosis by the Medium-Chain Length Fatty Acid Lauric Acid in Colon Cancer Cells due to Induction of Oxidative Stress
Authors: Fauser J.K. , Matthews G.M. , Cummins A.G. , Howarth G.S.
Published: December 2013

Background: Fatty acids are classified as short-chain (SCFA), medium-chain (MCFA) or long-chain and hold promise as adjunctive chemotherapeutic agents for the treatment of colorectal cancer. The antineoplastic potential of MCFA remains underexplored; accordingly, we compared the MCFA lauric acid (C12:0) to the SCFA butyrate (C4:0) in terms of their capacity to induce apoptosis, modify glutathione (GSH) levels, generate reactive oxygen species (ROS), and modify phases of the cell cycle in Caco-2 and IEC-6 intestinal cell lines. Methods: Caco-2 and IEC-6 cells were treated with lauric acid, butyrate, or vehicle controls. Apoptosis, ROS, and cell cycle analysis were determined by flow cytometry. GSH availability was assessed by enzymology. Results: Lauric acid induced apoptosis in Caco-2 (p < 0.05) and IEC-6 cells (p < 0.05) compared to butyrate. In Caco-2 cells, lauric acid reduced GSH availability and generated ROS compared to butyrate (p < 0.05). Lauric acid reduced Caco-2 and IEC-6 cells in G0/G1and arrested cells in the S and G2/M phases. Lauric acid induced apoptosis in IEC-6 cells compared to butyrate (p < 0.05). Butyrate protected IEC-6 cells from ROS-induced damage, whereas lauric acid induced high levels of ROS compared to butyrate. Conclusion: Compared to butyrate, lauric acid displayed preferential antineoplastic properties, including induction of apoptosis in a CRC cell line.
Alcohol-Induced Changes in Methylation Status of Individual CpG Sites, and Serum Levels of Vasopressin and Atrial Natriuretic Peptide in Alcohol-Dependent Patients during Detoxification Treatment
Authors: Glahn Alexander , Riera Knorrenschild Rafael , Rhein Mathias , Haschemi Nassab Mani , Gröschl Michael , Heberlein Annemarie , Muschler Marc , Frieling Helge , Bleich Stefan , Hillemacher Thomas
Published: December 2013

Disturbances of volume-regulating peptides like vasopressin (AVP) and atrial natriuretic peptide (ANP) have been described in early abstinent alcohol-dependent patients. In a longitudinal approach, we investigated whether changes in AVP and ANP serum levels correlated to cytosine-phosphatidyl-guanine (CpG) methylation of the respective gene promoters on days 1, 7 and 14 of alcohol withdrawal. We analyzed the blood samples of 99 patients suffering from alcohol dependence alongside age- and BMI-matched controls. Concerning AVP promoter methylation, we observed an interaction between time of measurement and CpG loci with CpG 2 showing a significant increase in methylation from day 1 to 14. Serum levels of AVP were significantly decreased in the patient group. Compared to healthy controls, promoter-related DNA methylation of the ANP promoter was significantly reduced on days 7 and 14. Moreover, we detected a significant interaction between CpG position and group. In both cases the difference was mainly observed at CpG 1. The present study shows significant changes in the methylation status of individual CpG sites of AVP and ANP. Observing respective alterations of AVP serum protein levels in alcohol-dependent patients during detoxification treatment, we consider methylation as a possible mode of regulation for these proteins during alcohol detoxification.
Laparoscopic Gastrectomy for Gastric Cancer with Peritoneal Dissemination after Induction Chemotherapy
Authors: Tsutsumi Satoshi , Oki Eiji , Ida Satoshi , Ando Koji , Kimura Yasue , Saeki Hiroshi , Morita Masaru , Kusumoto Tetsuya , Ikeda Tetsuo , Maehara Yoshihiko
Published: December 2013

Gastric cancer with peritoneal dissemination may be diagnosed as unresectable. More recently, as a result of progress in chemotherapy, some patients with peritoneal dissemination have exhibited extended survival. We report on our experience with three patients in whom induction chemotherapy allowed for totally laparoscopic total gastrectomy (TLTG). All three patients were diagnosed as having advanced gastric cancer with peritoneal dissemination using staging laparoscopy. As induction chemotherapy, S-1 combined with cisplatin was administered to two patients and trastuzumab plus capecitabine combined with cisplatin to one patient. TLTG was performed in all patients and there were no postoperative complications. Adjuvant chemotherapy was initiated within 3 weeks after surgery in all three patients. Laparoscopic gastrectomy undertaken after induction chemotherapy was found to be effective and safe; this treatment has the potential to achieve good treatment outcomes in patients with stage IV gastric cancer.
A contribuição da psicanálise para a atuação no campo da educação especial
Authors: Bernardino Leda Mariza Fischer
Published: December 2013

O artigo analisa as relações entre psicanálise e educação especial. O trabalho com crian ças com problemas de desenvolvimento requer o conhecimento do processo de constitui ção subjetiva e seu entrecruzamento com o desenvolvimento. Os conceitos psicanal íticos de sujeito e desejo, como eixos de um processo de reabilita ção, oferecem à criança um lugar de sujeito e não de objeto de técnicas ou treinamentos. Discute-se a questão da diferença, a partir do conceito de estranho familiar para Freud e as conseqüências clínicas desta abordagem. São apresentados exemplos de como a escuta psicanalítica promove este lugar de sujeito, tanto na clínica quanto em instituições.
Evaluation of Links Between High-Density Lipoprotein Genetics, Functionality, and Aortic Valve Stenosis Risk in Humans
Authors: Arsenault Benoit J. , Dubé Marie-Pierre , Brodeur Mathieu R. , de Oliveira Moraes Adriana Benjamin , Lavoie Véronique , Kernaleguen Anne-Elen , Guauque-Olarte Sandra , Mathieu Patrick , Pibarot Philippe , Messika-Zeitoun David , Bossé Yohan , Rhainds David , Rhéaume Éric , Tardif Jean-Claude
Published: December 2013

Objective—

Studies have shown that high-density lipoprotein (HDL)–raising compounds induce regression of aortic valve stenosis (AVS) in animal models. However, whether patients with AVS have an impaired HDL metabolism is unknown.

Approach and Results—

A total of 1435 single nucleotide polymorphisms in genes associated with HDL cholesterol levels (in or around
GALNT2, LPL, ABCA1, APOA5, SCARB1, LIPC, CETP, LCAT, LIPG, APOC4
, and
PLTP
) were genotyped in 382 patients with echocardiography-confirmed AVS (aortic jet velocity ≥2.5 m/s) and 401 controls. After control for multiple testing, none of the genetic variants showed a positive association with case/control status (adjusted
P
≥0.05 for all single nucleotide polymorphisms tested). In a subsample of this cohort, HDL cholesterol levels, apolipoprotein AI levels, lecithin-cholesterol acyltransferase activity, pre–β-HDL, HDL size, and 4 parameters of cholesterol efflux capacity were measured in apolipoprotein B–depleted serum samples from 86 patients with and 86 patients without AVS. Cholesterol efflux capacity was measured using J774 macrophages with and without stimulation of ATP-binding cassette A-1 expression by cAMP, and HepG2 hepatocytes for scavenger receptor class B type 1–mediated efflux. None of these parameters were different between cases and controls. However, compared with patients without coronary artery disease, sera from patients with coronary artery disease had lower HDL cholesterol levels, scavenger receptor class B type 1–mediated efflux, and HDL size (
P
≤0.003), independently of the presence or absence of AVS.

Conclusions—

Results of the present study suggest that, based on HDL genetics and HDL functionality, HDL metabolism does not seem to predict the risk of AVS. Because of our limited sample size, additional studies are needed to confirm these findings.
Infusion of Pharmaceutical-Grade Natural Human C-Reactive Protein Is Not Proinflammatory in Healthy Adult Human Volunteers
Authors: Lane Thirusha , Wassef Nancy , Poole Stephen , Mistry Yogesh , Lachmann Helen J. , Gillmore Julian D. , Hawkins Philip N. , Pepys Mark B.
Published: December 2013

Rationale
:

Baseline circulating concentrations of C-reactive protein (CRP) are significantly associated with cardiovascular disease risk in general populations. This modest association has been inappropriately conflated with causality, and it has been claimed that CRP is proatherogenic. Most of the known causative factors for atherosclerosis stimulate increased CRP production, but comprehensive genetic epidemiology studies provide no support for a pathogenic role of CRP. The reported proinflammatory effects of human CRP preparations on healthy cells in vitro and in healthy animals in vivo have all been produced by poorly characterized CRP preparations, demonstrably caused by impurities, or elicited by CRP made in recombinant
Escherichia coli
not by humans. None of the in vitro or animal findings have been reproduced with pure natural human CRP. Nevertheless, the strong proinflammatory effects of infusing recombinant bacterial CRP into humans have still been inappropriately ascribed to CRP.

Objective
:

To investigate the effects of infusion into healthy adult human volunteers of pure natural human CRP.

Methods and Results
:

Comprehensively characterized, pharmaceutical-grade, endotoxin-free, purified CRP, prepared to GMP standard from pooled normal human donor plasma was infused as an intravenous bolus in 7 healthy adult human volunteers at ≤2 mg/kg to provide circulating CRP concentrations ≤44 mg/L. No recipient showed any significant clinical, hematologic, coagulation, or biochemical changes, or any increase in proinflammatory cytokines or acute phase proteins.

Conclusions
:

The human CRP molecule itself is not proinflammatory in healthy human adults.
Macrophage Migration Inhibitory Factor Deficiency Augments Doxorubicin‐Induced Cardiomyopathy
Authors: Xu Xihui , Bucala Richard , Ren Jun
Published: December 2013

Background

Recent evidence has depicted a role of macrophage migration inhibitory factor (
MIF
) in cardiac homeostasis under pathological conditions. This study was designed to evaluate the role of
MIF
in doxorubicin‐induced cardiomyopathy and the underlying mechanism involved with a focus on autophagy.

Methods and Results

Wild‐type (WT) and
MIF
knockout (
MIF
−/−
) mice were given saline or doxorubicin (20 mg/kg cumulative, i.p.). A cohort of
WT
and
MIF
−/−
mice was given rapamycin (6 mg/kg, i.p.) with or without bafilomycin A1 (BafA1, 3 μmol/kg per day, i.p.) for 1 week prior to doxorubicin challenge. To consolidate a role for
MIF
in the maintenance of cardiac homeostasis following doxorubicin challenge, recombinant mouse
MIF
(
rmMIF
) was given to
MIF
−/−
mice challenged with or without doxorubicin. Echocardiographic, cardiomyocyte function, and intracellular Ca
2+
handling were evaluated. Autophagy and apoptosis were examined. Mitochondrial morphology and function were examined using transmission electron microscopy,
JC
‐1 staining, Mito
SOX
Red fluorescence, and mitochondrial respiration complex assay.
DHE
staining was used to evaluate
reactive oxygen species (ROS
) generation.
MIF
knockout exacerbated doxorubicin‐induced mortality and cardiomyopathy (compromised fractional shortening, cardiomyocyte and mitochondrial function, apoptosis, and
ROS
generation). These detrimental effects of doxorubicin were accompanied by defective autophagolysosome formation, the effect of which was exacerbated by
MIF
knockout. Rapamycin pretreatment rescued doxorubicin‐induced cardiomyopathy in
WT
and
MIF
−/−
mice. Blocking autophagolysosome formation using BafA1 negated the cardioprotective effect of rapamycin and
rmMIF
.

Conclusions

Our data suggest that
MIF
serves as an indispensable cardioprotective factor against doxorubicin‐induced cardiomyopathy with an underlying mechanism through facilitating autophagolysosome formation.
Rad GTPase Deletion Increases L‐type Calcium Channel Current Leading to Increased Cardiac Contraction
Authors: Manning Janet R. , Yin Guo , Kaminski Catherine N. , Magyar Janos , Feng Han‐Zhong , Penn John , Sievert Gail , Thompson Katherine , Jin J.‐P. , Andres Douglas A. , Satin Jonathan
Published: December 2013

Background

The small
GTP
ase Rad is a negative regulator of voltage‐dependent L‐type calcium channel current (

I
C

aL
); however, the effects of Rad ablation on cardiomyocyte function are unknown. The objective of this study is to test the hypothesis that Rad‐depletion causes positive inotropic effects without inducing cardiac hypertrophy.

Methods and Results

Ventricular myocytes from adult Rad
−/−
mice were isolated and evaluated by patch‐clamp recordings for I
Ca,L
and action potentials, Ca
2+
transients, and sarcomere shortening. Maximum I
CaL
is elevated in Rad
−/−
(maximal conductance 0.35±0.04 picoSiemens/picoFarad (
pS
/
pF
) wild‐type; 0.61±0.14 
pS
/
pF
Rad
−/−
), decay kinetics are faster, and I
Ca,L
activates at lower voltages (activation midpoint −7.2±0.6 wild‐type; −11.7±0.9 Rad
−/−
) mimicking effects of β‐adrenergic receptor stimulation. Diastolic and twitch calcium are elevated in Rad
−/−
(
F
340/380
: 1.03 diastolic and 0.35 twitch for wild‐type; 1.47 diastolic and 0.736 twitch for Rad
−/−
) and sarcomere shortening is enhanced (4.31% wild‐type; 14.13% Rad
−/−
) at lower pacing frequencies. Consequentially, frequency‐dependence of Ca
2+
transients is less in Rad
−/−
, and the frequency dependence of relaxation is also blunted. In isolated working hearts, similar results were obtained; chiefly, +
dP
/dt was elevated at baseline and developed pressure was relatively nonresponsive to acute β‐adrenergic receptor stimulation. In single cells, at subphysiological frequencies, nonstimulated calmodulin‐dependent protein kinase–sensitive calcium release is observed. Remarkably, Rad
−/−
hearts did not show hypertrophic growth despite elevated levels of diastolic calcium.

Conclusions

This study demonstrates that the depletion of Rad
GTP
ase is equivalent to sympathomimetic β‐adrenergic receptor, without stimulating cardiac hypertrophy. Thus, targeting Rad
GTP
ase is a novel potential therapeutic target for Ca
2+
‐homeostasis–driven positive inotropic support of the heart.
Alberta Stroke Program Early Computed Tomography Score to Select Patients for Endovascular Treatment
Authors: Hill Michael D. , Demchuk Andrew M. , Goyal Mayank , Jovin Tudor G. , Foster Lydia D. , Tomsick Thomas A. , von Kummer Rüdiger , Yeatts Sharon D. , Palesch Yuko Y. , Broderick Joseph P.
Published: December 2013

Background and Purpose—

The Interventional Management of Stroke (IMS)-III trial randomized patients with acute ischemic stroke to intravenous tissue-type plasminogen activator (tPA) plus endovascular therapy versus intravenous tPA therapy alone within 3 hours from symptom onset. A predefined secondary hypothesis was that subjects with significant early ischemic change on the baseline scan would not respond to endovascular therapy.

Methods—

The primary outcome was 90-day modified Rankin Scale score 0 to 2. The baseline and follow-up computed tomographic (CT) scan images were reviewed centrally and blinded to any clinical information. We assessed whether the baseline Alberta Stroke Program Early CT Score (ASPECTS) predicted outcome and interacted with study treatment. We analyzed subgroups defined by time from onset to intravenous tPA initiation and baseline occlusion status at a prespecified α=0.01.

Results—

Baseline demographic and clinical characteristics of 656 randomized patients were similar between subjects with a baseline ASPECTS 8 to 10 (58% of the study sample) versus 0 to 7. Subjects with ASPECTS 8 to 10 were almost twice as likely (relative risk, 1.8; 99% confidence interval, 1.4–2.4) to achieve a favorable outcome. There was insufficient evidence of a treatment-by-ASPECTS interaction. In those treated with onset to intravenous tPA <120 minutes, in CT angiography–proven internal carotid artery or middle cerebral artery occlusion, and in both, results were similar. The probability of achieving recanalization (arterial occlusion lesion, 2–3) of the primary arterial occlusive lesion (relative risk, 1.3; 99% confidence interval, 1.0–1.8) or achieving thrombolysis in cerebral ischemia score 2b/3 reperfusion (relative risk 2.0; 99% confidence interval, 1.2–3.2) was higher among subjects with higher ASPECTS.

Conclusions—

ASPECTS is a strong predictor of outcome and a predictor of reperfusion. ASPECTS did not identify a subpopulation of subjects that particularly benefitted from endovascular therapy immediately after routine intravenous tPA.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT00359424.
Planothidium galaicum sp. nov. (Bacillariophyta, Achnanthidiaceae), a new diatom species from Galician coast, Spain
Authors: ÁLVAREZ-BLANCO IRENE , BLANCO SAÚL
Published: December 2013

A new Planothidium species, Planothidium galaicum sp. nov. is described on the basis of light and electron microscopy investigations of its frustule morphology. This diatom was found in the epiphyton of Himanthalia elongata at Muxía coast (Galicia, northwest Spain). A discussion of the morphological features of this taxon and their taxonomic affinities with related species, is presented.