bluuebunny/crossref_metadata_2025 huggingface dataset:
Physical properties of the Yaxcopoil‐1 deep drill core, Chicxulub impact structure, Mexico
Authors: ELBRA Tiiu , PESONEN Lauri J.
Published: October 2011

Abstract– The Chicxulub structure in Mexico, one of the largest impact structures on Earth, was formed 65 Ma by a hypervelocity impact that led to the large mass extinction at the K‐Pg boundary. The Chicxulub impact structure is well preserved, but is buried beneath a sequence of carbonate sediments and, thus, requires drilling to obtain subsurface information. The Chicxulub Scientific Drilling Program was carried out at Hacienda Yaxcopoil in the framework of the International Continental Scientific Drilling Program in 2001–2002. The structure was cored from 404 m down to 1511 m, through three intervals: 794 m of postimpact Tertiary sediments, a 100 m thick impactite sequence, and 616 m of preimpact Cretaceous rocks thought to represent a suite of megablocks. Physical property investigations show that the various lithologies, including the impactite units and the K‐Pg boundary layer, can be characterized by their physical properties, which depend on either changes in fabric or on mineralogical variations. The magnetic properties show mostly dia‐ or paramagnetic behavior, with the exception of the impactite units that indicate the presence of ferromagnetic, probably hydrothermally deposited magnetite and pyrrhotite. The magnetic fraction contributes mainly to enhanced magnetization in the impactite lithologies and, in this way, to the observed magnetic anomalies. The shape and orientation of the magnetic grains are varied and reflect inhomogeneous fabric development and the influence of impact‐related redeposition and hydrothermal activity. The Chicxulub impact occurred at the time of the reverse polarity geomagnetic chron 29R, and this finding is consistent with the age of the K‐Pg boundary.
Rock magnetic and paleomagnetic study of the Keurusselkä impact structure, central Finland
Authors: RAISKILA Selen , SALMINEN Johanna , ELBRA Tiiu , PESONEN Lauri J.
Published: October 2011

Abstract–There are 31 proven impact structures in Fennoscandia—one of the most densely crater‐populated areas of the Earth. The recently discovered Keurusselkä impact structure (62°08′ N, 24°37′ E) is located within the Central Finland Granitoid Complex, which formed 1890–1860 Ma ago during the Svecofennian orogeny. It is a deeply eroded complex crater that yields in situ shatter cones with evidence of shock metamorphism, e.g., planar deformation features in quartz. New petrophysical and rock magnetic results of shocked and unshocked target rocks of various lithologies combined with paleomagnetic studies are presented. The suggested central uplift with shatter cones is characterized by increased magnetization and susceptibility. The presence of magnetite and pyrrhotite was observed as carriers for the remanent magnetization. Four different remanent magnetization directions were isolated: (1) a characteristic Svecofennian target rock component A with a mean direction ofD = 334.8°,I = 45.6°, α95 = 14.9° yielding a pole (Plat = 51.1°, Plon = 241.9°,A95 = 15.1°), (2) component B,D = 42.4°,I = 64.1°, α95 = 8.4° yielding a pole (Plat = 61.0°, Plon = 129.1°,A95 = 10.6°), (3) component C (D = 159.5°,I= 65.4°, α95 = 10.7°) yielding a pole (Plat = 21.0°, Plon = 39.3°,A95 = 15.6°), and (4) component E (D = 275.5°,I = 62.0°, α95 = 14.4°) yielding a pole (Plat = 39.7°, Plon = 314.3°,A95 = 19.7°). Components C and E are considered much younger, possibly Neoproterozoic overprints, compared with the components A and B. The pole of component B corresponds with the 1120 Ma pole of Salla diabase dyke and is in agreement with the40Ar/39Ar age of 1140 Ma from a pseudotachylitic breccia vein in a central part of the structure. Therefore, component B could be related to the impact, and thus represent the impact age.
The molecular epidemiology of equine influenza in Ireland from 2007–2010 and its international significance
Authors: GILDEA S. , QUINLIVAN M. , ARKINS S. , CULLINANE A.
Published: October 2011

Reasons for performing the study: Antigenic and genetic drift of equine influenza (EI) virus is monitored annually by the Expert Surveillance Panel (ESP), which make recommendations on the need to update vaccines. Surveillance programmes are essential for this process to operate effectively and to decrease the risk of disease spread through the international movement of subclinically infected vaccinated horses. Not only is surveillance necessary to inform vaccine companies which strains are in circulation, but it serves as an early warning system for horse owners, trainers and veterinary clinicians, facilitating the implementation of appropriate prophylactic and control measures.

Objective: To summarise the genetic analysis of EI viruses detected in Ireland from June 2007 to January 2010.

Methods: The HA1 gene of 18 viruses was sequenced and phylogenetic analysis undertaken.

Results: All viruses belonged to the Florida sublineage of the American lineage. Clade 2 viruses predominated up to 2009. The viruses identified on 4 premises in 2007 displayed 100% nucleotide identity to A/eq/Richmond/1/07, the current clade 2 prototype. The first clade 1 virus was identified in November 2009 and, thereafter, clade 1 viruses were responsible for all the outbreaks identified. The Irish clade 1 viruses differ from the clade 1 virus responsible for the EI outbreaks in Japan and Australia in 2007. No virus of the Eurasian lineage was isolated during this surveillance period.

Conclusions: In 2010 the ESP recommended that the vaccines should not include a H7N7 virus or a H3N8 virus of the Eurasian lineage but that they should contain both a clade 1 and clade 2 virus of the Florida sublineage. The surveillance data presented here support these recommendations and indicate that they are epidemiologically relevant.

Potential relevance: These data also serve as a scientific basis for investigating the source of epizootics and outbreaks both nationally and internationally.
A grounded theory approach to understand the cancer‐coping process
Authors: Knott Vikki , Turnbull Deborah , Olver Ian , Winefield Anthony
Published: October 2011

Objectives. A focus on individualistic coping strategies such as positivity and fighting spirit has done little to inform the development of interventions for people affected by cancer. The aim of this study was to conduct an inquiry, which focused on the ‘lived experience’ and the social context within which communication about cancer occurs.

Design. A semi‐structured interview schedule was used. These interviews were complemented by the Mini‐International Neuropsychiatric Interview (M.I.N.I., Sheehan et al., 1998).

Methods. Twenty participants with mixed diagnoses (13 female and seven male), ranging in age from 44 to 73 (Mean = 58.35, SD= 8.20) were interviewed. Consistent with Glaser's (1992) constant comparative method, research data were open coded, selectively coded, and then theoretically coded so that initial codes were collapsed into models and compared against existing literature for completeness.

Results. Fifty percent of participants met criteria for an Axis 1 diagnosis. Three models emerged from the research interview; the first provides a description of the way in which patients evaluate the quality of care they receive across the cancer pathway. Other models refer to the cancer‐coping process in which participants describe successful and unsuccessful attempts at coping via communication and whereby coping with cancer is characterized by a series of losses accompanied by increased distress.

Conclusions. A research focus on the social environment in which cancer is experienced provides considerable insight into the cancer‐coping process. As such, interventions focused on understanding the social context in which patients experience cancer, and attempt to cope, may facilitate improved adjustment for those directly, and potentially indirectly, affected by cancer. Further research is required to develop interventions to address the unique needs of survivors.
Recalled peer relationship experiences and current levels of self‐criticism and self‐reassurance
Authors: Kopala‐Sibley Daniel C. , Zuroff David C. , Leybman Michelle J. , Hope Nora
Published: October 2011

Objectives. Numerous studies have shown that personality factors may increase or decrease individuals’ vulnerability to depression, but little research has examined the role of peer relationships in the development of these factors. Accordingly, this study examined the role of recalled parenting and peer experiences in the development of self‐criticism and self‐reassurance. It was hypothesized that, controlling for recalled parenting behaviours, specific recalled experiences of peer relationships would be related to current levels of specific forms of self‐criticism and self‐reassurance.

Design. Hypotheses were tested using a retrospective design in which participants were asked to recall experiences of parenting and peer relationships during early adolescence. This age was chosen as early adolescence has been shown to be a critical time for the development of vulnerability to depression.

Methods. A total of 103 female and 97 male young adults completed measures of recalled parenting, overt and relational victimization and prosocial behaviour by peers, and current levels of self‐criticism and self‐reassurance.

Results. Hierarchical regression analyses showed that parents and peers independently contributed to the development of self‐criticism and self‐reassurance. Specifically, controlling for parental care and control, overt victimization predicted self‐hating self‐criticism, relational victimization predicted inadequacy self‐criticism, and prosocial behaviour predicted self‐reassurance. As well, prosocial behaviour buffered the effect of overt victimization on self‐reassurance.

Conclusions. Findings highlight the importance of peers in the development of personality risk and resiliency factors for depression, and suggest avenues for interventions to prevent the development of depressive vulnerabilities in youth.

Practitioner points

The nature of a patient's personality vulnerability to depression may be better understood through a consideration of the patient's relationships with their peers as well as with parents during adolescence.

An understanding of adult patients’ past peer relationships may further the therapist's understanding of the client's core schemas and dysfunctional attitudes, as well as potential transference reactions during therapy.

Identifying and helping youth to better cope with peer victimization may help prevent the development of a vulnerable personality style in adulthood.

Fostering positive peer relationships in adolescence may buffer the effects of other more negative relationships with peers.
Lithospheric Thinning Beneath Rifted Regions of Southern California
Authors: Lekic Vedran , French Scott W. , Fischer Karen M.
Published: October 2011

Seismic imaging reveals the degree to which extensional forces can pull apart the lithosphere.
Complete Genome Sequence of a Chinese Virulent Porcine Epidemic Diarrhea Virus Strain
Authors: Chen Jianfei , Wang Chengbao , Shi Hongyan , Qiu Hua-Ji , Liu Shengwang , Shi Da , Zhang Xin , Feng Li
Published: October 2011

CH/S is a virulent porcine epidemic diarrhea virus (PEDV) strain and is used as the virulent strain to evaluate the protection rates of vaccines against PEDV infection in China. Here, we report the complete genome sequence of strain CH/S, which may aid in understanding the molecular characteristics of this strain.
Evaluation of a new model of short-term palliative care for people severely affected with multiple sclerosis: a randomised fast-track trial to test timing of referral and how long the effect is maintained
Authors: Higginson Irene J , Costantini Massimo , Silber Eli , Burman Rachel , Edmonds Polly
Published: October 2011

Aims

In this randomised fast-track phase II trial, the authors examined (1) whether the timing of referral to short-term palliative care (PC) affected selected outcomes, and (2) the potential staff-modifying effect of the short-term PC intervention (whether the effects were sustained over time after PC was withdrawn).

Methods

PC comprised a multiprofessional PC team that provided, on average, three visits, with all care completed by 6 weeks. Recruitment commenced in August 2004 and continued for 1 year. Follow-up was performed for 6 months in both groups. Outcomes were a composite measure of five key symptoms (pain, nausea, vomiting, mouth problems and sleeping difficulty) using the Palliative care Outcome Scale–MS Symptom Scale, and care giver burden was measured using the Zarit (Care Giver) Burden Interview (ZBI).

Results

52 patients severely affected by multiple sclerosis were randomised to receive PC either immediately (fast-track group) or after 12 weeks (control group). Patients had a high level of disability (mean Expanded Disability Status Scale: 7.7; median: 8; SD: 1). Following PC, there was an improvement in Palliative care Outcome Scale–MS Symptom Scale score and ZBI score. A higher rate of improvement in ZBI score was seen in the fast-track group. After withdrawal of PC, effects were maintained at 12 weeks, but not at 24 weeks.

Conclusions

Receiving PC earlier has a similar effect on reducing symptoms but greater effects on reducing care giver burden, compared to later referral. In this phase II trial, the authors lacked the power to detect small differences. The effect of PC is maintained for 6 weeks after withdrawal but then appears to wane.

Trial Registration Number

National Institutes of Health, USA, http://www.Clinicaltrials.gov, NCT00364936.
Altered calcium signaling in colonic smooth muscle of type 1 diabetic mice
Authors: Touw Ketrija , Chakraborty Saikat , Zhang Wenwu , Obukhov Alexander G. , Tune Johnathan D. , Gunst Susan J. , Herring B. Paul
Published: October 2011

Seventy-six percent of diabetic patients develop gastrointestinal symptoms, such as constipation. However, the direct effects of diabetes on intestinal smooth muscle are poorly described. This study aimed to identify the role played by smooth muscle in mediating diabetes-induced colonic dysmotility. To induce type 1 diabetes, mice were injected intraperitoneally with low-dose streptozotocin once a day for 5 days. Animals developed hyperglycemia (>200 mg/dl) 1 wk after the last injection and were euthanized 7–8 wk after the last treatment. Computed tomography demonstrated decreased overall gastrointestinal motility in the diabetic mice. In vitro contractility of colonic smooth muscle rings from diabetic mice was also decreased. Fura-2 ratiometric Ca2+imaging showed attenuated Ca2+increases in response to KCl stimulation that were associated with decreased light chain phosphorylation in diabetic mice. The diabetic mice also exhibited elevated basal Ca2+levels, increased myosin phosphatase targeting subunit 1 expression, and significant changes in expression of Ca2+handling proteins, as determined by quantitative RT-PCR and Western blotting. Mice that were hyperglycemic for <1 wk also showed decreased colonic contractile responses that were associated with decreased Ca2+increases in response to KCl stimulation, although without an elevation in basal Ca2+levels or a significant change in the expression of Ca2+signaling molecules. These data demonstrate that type 1 diabetes is associated with decreased depolarization-induced Ca2+influx in colonic smooth muscle that leads to attenuated myosin light chain phosphorylation and impaired colonic contractility.
The effect of physiological concentrations of caffeine on the power output of maximally and submaximally stimulated mouse EDL (fast) and soleus (slow) muscle
Authors: Tallis Jason , James Rob S. , Cox Val M. , Duncan Michael J.
Published: October 2011

The ergogenic effects of caffeine in human exercise have been shown to improve endurance and anaerobic exercise performance. Previous work has demonstrated that 70 μM caffeine (physiological maximum) can directly increase mouse extensor digitorum longus (EDL) muscle power output (PO) in sprintlike activity by 3%. Our study used the work loop technique on isolated mouse muscles to investigate whether the direct effect of 70 μM caffeine on PO differed between 1) maximally and submaximally activated muscle; 2) relatively fast (EDL) and relatively slow (soleus) muscles; and 3) caffeine concentrations. Caffeine treatment of 70 μM resulted in significant improvements in PO in maximally and submaximally activated EDL and soleus ( P < 0.03 in all cases). For EDL, the effects of caffeine were greatest when the lowest, submaximal stimulation frequency was used ( P < 0.001). Caffeine treatments of 140, 70, and 50 μM resulted in significant improvements in acute PO for both maximally activated EDL (3%) and soleus (6%) ( P < 0.023 in all cases); however, there was no significant difference in effect between these concentrations ( P > 0.420 in all cases). Therefore, the ergogenic effects of caffeine on PO were higher in muscles with a slower fiber type ( P < 0.001). Treatment with 35 μM caffeine failed to elicit any improvement in PO in either muscle ( P > 0.72 in both cases). Caffeine concentrations below the physiological maximum can directly potentiate skeletal muscle PO. This caffeine-induced increase in force could provide similar benefit across a range of exercise intensities, with greater gains likely in activities powered by slower muscle fiber type.
Host Response to Short-term, Single-Agent Chemotherapy Induces Matrix Metalloproteinase-9 Expression and Accelerates Metastasis in Mice
Authors: Gingis-Velitski Svetlana , Loven David , Benayoun Liat , Munster Michal , Bril Rotem , Voloshin Tali , Alishekevitz Dror , Bertolini Francesco , Shaked Yuval
Published: October 2011

Mounting evidence suggests that bone marrow–derived cells (BMDC) contribute to tumor growth, angiogenesis, and metastasis. In acute reactions to cancer therapy, several types of BMDCs are rapidly mobilized to home tumors. Although this host reaction to therapy can promote tumor regrowth, its contribution to metastasis has not been explored. To focus only on the effects of chemotherapy on the host, we studied non–tumor-bearing mice. Plasma from animals treated with the chemotherapy paclitaxel induced angiogenesis, migration, and invasion of tumor cells along with host cell colonization. Lesser effects were seen with the chemotherapy gemcitabine. Conditioned medium from BMDCs and plasma from chemotherapy-treated mice each promoted metastatic properties in tumor cells by inducing matrix metalloproteinase-9 (MMP9) and epithelial-to-mesenchymal transition. In mice in which Lewis lung carcinoma cells were injected intravenously, treatment with paclitaxel, but not gemcitabine or vehicle, accelerated metastases in a manner that could be blocked by an MMP9 inhibitor. Moreover, chimeric mice reconstituted with BMDC where MMP9 activity was attenuated did not support accelerated metastasis by carcinoma cells that were pretreated with chemotherapy before their introduction to host animals. Taken together, our findings illustrate how some chemotherapies can exert prometastatic effects that may confound treatment outcomes. Cancer Res; 71(22); 6986–96. ©2011 AACR.
Cooperative Phosphorylation of FADD by Aur-A and Plk1 in Response to Taxol Triggers Both Apoptotic and Necrotic Cell Death
Authors: Jang Moon-Sun , Lee Su-Jin , Kang Nam Sook , Kim Eunhee
Published: October 2011

Administration of the antimitotic chemotherapeutic taxol is known to cause accumulation of the mitotic kinase Aurora-A (Aur-A). Here, we report that Aur-A phosphorylates S203 of the Fas associated with death domain protein (FADD) in response to taxol treatment. In addition, polo-like kinase 1 (Plk1) failed to phosphorylate the Aur-A–unphosphorylatable FADD substitution mutant S203A, indicating that phosphorylation of S203 by Aur-A serves to prime FADD for Plk1-mediated phosphorylation at S194. The double-phosphorylation-mimicking mutant form of FADD, FADD-S194D/S203D (FADD-DD), recruited caspase-8, activating the caspase-dependent cell death pathway. FADD-DD also dissociated the cell death protein RIP1 from FADD, resulting in activation of RIP1 and triggering of caspase-independent cell death. Consistent with its death-promoting potential, FADD-DD showed robust tumor suppressor activity. However, single-phosphorylation-mimicking mutant forms of FADD, FADD-S194D/S203A (FADD-DA) and FADD-S194A/S203D (FADD-AD), were incapable of carrying out such functions, indicating that double phosphorylation of FADD is critical for the execution of cell death and tumor suppression. Collectively, our data show the existence of cooperative actions between Aur-A and Plk1 mitotic kinases in response to taxol, providing a molecular explanation for the action mechanism of taxol. Cancer Res; 71(23); 7207–15. ©2011 AACR.
Epigenetic Alteration of PRKCDBP in Colorectal Cancers and Its Implication in Tumor Cell Resistance to TNFα-Induced Apoptosis
Authors: Lee Jin-Hee , Kang Min-Ju , Han Hye-Yeon , Lee Min-Goo , Jeong Seong-In , Ryu Byung-Kyu , Ha Tae-Kyu , Her Nam-Goo , Han Jikhyon , Park Sun Jin , Lee Kil Yeon , Kim Hyo-Jong , Chi Sung-Gil
Published: October 2011

Purpose: PRKCDBP is a putative tumor suppressor in which alteration has been observed in several human cancers. We investigated expression and function of PRKCDBP in colorectal cells and tissues to explore its candidacy as a suppressor in colorectal tumorigenesis.

Experimental Design: Expression and methylation status of PRKCDBP and its effect on tumor growth were evaluated. Transcriptional regulation by NF-κB signaling was defined by luciferase reporter and chromatin immunoprecipitation assays.

Results: PRKCDBP expression was hardly detectable in 29 of 80 (36%) primary tumors and 11 of 19 (58%) cell lines, and its alteration correlated with tumor stage and grade. Promoter hypermethylation was commonly found in cancers. PRKCDBP expression induced the G1 cell-cycle arrest and increased cellular sensitivity to various apoptotic stresses. PRKCDBP was induced by TNFα, and its level correlated with tumor cell sensitivity to TNFα-induced apoptosis. PRKCDBP induction by TNFα was disrupted by blocking NF-κB signaling while it was enhanced by RelA transfection. The PRKCDBP promoter activity was increased in response to TNFα, and this response was abolished by disruption of a κB site in the promoter. PRKCDBP delayed the formation and growth of xenograft tumors and improved tumor response to TNFα-induced apoptosis.

Conclusions: PRKCDBP is a proapoptotic tumor suppressor which is commonly altered in colorectal cancer by promoter hypermethylation, and its gene transcription is directly activated by NF-κB in response to TNFα. This suggests that PRKCDBP inactivation may contribute to tumor progression by reducing cellular sensitivity to TNFα and other stresses, particularly under chronic inflammatory microenvironment. Clin Cancer Res; 17(24); 7551–62. ©2011 AACR.
Cytoplasmic Estrogen Receptor in Breast Cancer
Authors: Welsh Allison W. , Lannin Donald R. , Young Gregory S. , Sherman Mark E. , Figueroa Jonine D. , Henry N. Lynn , Ryden Lisa , Kim Chungyeul , Love Richard R. , Schiff Rachel , Rimm David L.
Published: October 2011

Purpose: In addition to genomic signaling, it is accepted that estrogen receptor-α (ERα) has nonnuclear signaling functions, which correlate with tamoxifen resistance in preclinical models. However, evidence for cytoplasmic ER localization in human breast tumors is less established. We sought to determine the presence and implications of nonnuclear ER in clinical specimens.

Experimental Design: A panel of ERα-specific antibodies (SP1, MC20, F10, 60c, and 1D5) was validated by Western blot and quantitative immunofluorescent (QIF) analysis of cell lines and patient controls. Then eight retrospective cohorts collected on tissue microarrays were assessed for cytoplasmic ER. Four cohorts were from Yale (YTMA 49, 107, 130, and 128) and four others (NCI YTMA 99, South Swedish Breast Cancer Group SBII, NSABP B14, and a Vietnamese Cohort) from other sites around the world.

Results: Four of the antibodies specifically recognized ER by Western and QIF analysis, showed linear increases in amounts of ER in cell line series with progressively increasing ER, and the antibodies were reproducible on YTMA 49 with Pearson correlations (r2 values) ranging from 0.87 to 0.94. One antibody with striking cytoplasmic staining (MC20) failed validation. We found evidence for specific cytoplasmic staining with the other four antibodies across eight cohorts. The average incidence was 1.5%, ranging from 0 to 3.2%.

Conclusions: Our data show ERα is present in the cytoplasm in a number of cases using multiple antibodies while reinforcing the importance of antibody validation. In nearly 3,200 cases, cytoplasmic ER is present at very low incidence, suggesting its measurement is unlikely to be of routine clinical value. Clin Cancer Res; 18(1); 118–26. ©2011 AACR.
Lysosomal Sequestration of Sunitinib: A Novel Mechanism of Drug Resistance
Authors: Gotink Kristy J. , Broxterman Henk J. , Labots Mariette , de Haas Richard R. , Dekker Henk , Honeywell Richard J. , Rudek Michelle A. , Beerepoot Laurens V. , Musters René J. , Jansen Gerrit , Griffioen Arjan W. , Assaraf Yehuda G. , Pili Roberto , Peters Godefridus J. , Verheul Henk M.W.
Published: October 2011

Purpose: Resistance to antiangiogenic tyrosine kinase inhibitors such as sunitinib is an important clinical problem, but its underlying mechanisms are largely unknown. We analyzed tumor sunitinib levels in mice and patients and studied sensitivity and resistance mechanisms to sunitinib.

Experimental Design: Intratumoral and plasma sunitinib concentrations in mice and patients were determined. Sunitinib exposure on tumor cell proliferation was examined. Resistant tumor cells were derived by continuous exposure and studied for alterations in intracellular sunitinib accumulation and activity.

Results: Intratumoral concentrations of sunitinib in mice and patients were 10.9 ± 0.5 and 9.5 ± 2.4 μmol/L, respectively, whereas plasma concentrations were 10-fold lower, 1.0 ± 0.1 and 0.3 ± 0.1 μmol/L, respectively. Sunitinib inhibited tumor cell growth at clinically relevant concentrations in vitro, with IC50 values of 1.4 to 2.3 μmol/L. Continuous exposure to sunitinib resulted in resistance of 786-O renal and HT-29 colon cancer cells. Fluorescent microscopy revealed intracellular sunitinib distribution to acidic lysosomes, which were significantly higher expressed in resistant cells. A 1.7- to 2.5-fold higher sunitinib concentration in resistant cells was measured because of increased lysosomal sequestration. Despite the higher intracellular sunitinib accumulation, levels of the key signaling p-Akt and p-ERK 1/2 were unaffected and comparable with untreated parental cells, indicating reduced effectiveness of sunitinib.

Conclusion: We report that sunitinib inhibits tumor cell proliferation at clinically relevant concentrations and found lysosomal sequestration to be a novel mechanism of sunitinib resistance. This finding warrants clinical evaluation whether targeting lysosomal function will overcome sunitinib resistance. Clin Cancer Res; 17(23); 7337–46. ©2011 AACR.
Direct Role of Adiponectin and Adiponectin Receptors in Endometrial Cancer: In Vitro and Ex Vivo Studies in Humans
Authors: Moon Hyun-Seuk , Chamberland John P. , Aronis Konstantinos , Tseleni-Balafouta Sofia , Mantzoros Christos S.
Published: October 2011

Low adiponectin levels are an independent risk factor for and mediate the effect of obesity on endometrial cancer in epidemiology studies. The direct or indirect mechanisms underlying these findings remain to be elucidated. We first examined the expression of adiponectin receptor 1 (AdipoR1) and 2 (AdipoR2) in normal human endometrium and in endometrial cancer tissues ex vivo. We then used KLE and RL95-2 human endometrial cancer cell lines in vitro to study relative expression of AdipoRs, to investigate the effect of adiponectin on activating intracellular signaling pathways, and to assess its potential to alter malignant properties. We report for the first time that the relative expression level of AdipoR1 is higher than AdipoR2 in human endometrial cancer tissue, but the expression of AdipoRs is not statistically different from nonneoplastic tissues. We also show for the first time in endometrial cancer cell lines in vitro that adiponectin suppresses endometrial cancer proliferation acting through AdipoRs. Adiponectin also increases the expression of the adaptor molecule LKB1, which is required for adiponectin-mediated activation of AMPK/S6 axis and modulation of cell proliferation, colony formation, adhesion, and invasion of KLE and RL95-2 cell lines. These novel mechanistic studies provide for the first time in vitro and ex vivo evidence for a causal role of adiponectin in endometrial cancer. Mol Cancer Ther; 10(12); 2234–43. ©2011 AACR.
Spatial Distribution and Mechanical Function of Elastin in Resistance Arteries
Authors: Clifford Philip S. , Ella Srikanth R. , Stupica Aaron J. , Nourian Zahra , Li Min , Martinez-Lemus Luis A. , Dora Kim A. , Yang Yan , Davis Michael J. , Pohl Ulrich , Meininger Gerald A. , Hill Michael A.
Published: October 2011

Objective—

Despite the role that extracellular matrix (ECM) plays in vascular signaling, little is known of the complex structural arrangement between specific ECM proteins and vascular smooth muscle cells. Our objective was to examine the hypothesis that adventitial elastin fibers are dominant in vessels subject to longitudinal stretch.

Methods and Results—

Cremaster muscle arterioles were isolated, allowed to develop spontaneous tone, and compared with small cerebral arteries. 3D confocal microscopy was used to visualize ECM within the vessel wall. Pressurized arterioles were fixed and stained with Alexa 633 hydrazide (as a nonselective ECM marker), anti-elastin, or anti-type 1 collagen antibody and a fluorescent nuclear stain. Exposure of cremaster muscle arterioles to elastase for 5 minutes caused an irreversible lengthening of the vessel segment that was not observed in cerebral arteries. Longitudinal elastin fibers were demonstrated on cremaster muscle arterioles using 3D imaging but were confirmed to be absent in cerebral vessels. The fibers were also distinct from type I collagen fibers and were degraded by elastase treatment.

Conclusion—

These results indicate the importance of elastin in bearing longitudinal stress in the arteriolar wall and that these fibers constrain vascular smooth muscle cells. Differences between skeletal muscle and cerebral small arteries may reflect differences in the local mechanical environment, such as exposure to longitudinal stretch.
Abcc6
Deficiency Causes Increased Infarct Size and Apoptosis in a Mouse Cardiac Ischemia-Reperfusion Model
Authors: Mungrue Imran N. , Zhao Peng , Yao Yucheng , Meng Haijin , Rau Christoph , Havel Jocelyn V. , Gorgels Theo G.M.F. , Bergen Arthur A.B. , MacLellan W. Robb , Drake Thomas A. , Boström Kristina I. , Lusis Aldons J.
Published: October 2011

Objective—

ABCC6
genetic deficiency underlies pseudoxanthoma elasticum (PXE) in humans, characterized by ectopic calcification, and early cardiac disease. The spectrum of PXE has been noted in
Abcc6
-deficient mice, including dystrophic cardiac calcification. We tested the role of
Abcc6
in response to cardiac ischemia-reperfusion (I/R) injury.

Methods and Results—

To determine the role of
Abcc6
in cardioprotection, we induced ischemic injury in mice in vivo by occluding the left anterior descending artery (30 minutes) followed by reperfusion (48 hours). Infarct size was increased in
Abcc6
-deficient mice compared with wild-type controls. Additionally, an Abcc6 transgene significantly reduced infarct size on the background of a naturally occurring
Abcc6
deficiency. There were no differences in cardiac calcification following I/R, but increased cardiac apoptosis was noted in
Abcc6
-deficient mice. Previous studies have implicated the bone morphogenetic protein (BMP) signaling pathway in directing calcification, and here we showed that the BMP responsive transcription factors pSmad1/5/8 were increased in hearts of
Abcc6
mice. Consistent with this finding, BMP4 and BMP9 were increased and activin receptor-like kinase-2 and endoglin were downregulated in cardiac extracts from
Abcc6
-deficient mice versus controls.

Conclusion—

These data identify
Abcc6
as a novel modulator of cardiac myocyte survival after I/R. This cardioprotective mechanism may involve inhibition of the BMP signaling pathway, which modulates apoptosis.
Transforming Growth Factor-β Signaling in Myogenic Cells Regulates Vascular Morphogenesis, Differentiation, and Matrix Synthesis
Authors: Jaffe Mia , Sesti Casilde , Washington Ida M. , Du Liang , Dronadula Nagadhara , Chin Michael T. , Stolz Donna B. , Davis Elaine C. , Dichek David A.
Published: October 2011

Objective—

Transforming growth factor-β (TGF-β) signaling is required for normal vascular development. We aimed to discover the role of TGF-β signaling in embryonic smooth muscle cells (SMCs).

Methods and Results—

We bred mice with smooth muscle (SM) 22α-Cre and
Tgfbr2
flox
alleles to generate embryos in which the type II TGF-β receptor (TGFBR2; required for TGF-β signaling) was deleted in SMCs. Embryos were harvested between embryonic day (E) 9.5 and E18.5 and examined grossly, microscopically, and by histochemical and RNA analyses. SM22α-Cre
+/0
Tgfbr2
flox/flox
(knockout [KO]) embryos died before E15.5 with defects that included cardiac outflow tract abnormalities, persistence of the right dorsal aorta, and dilation of the distal aorta. Histological analyses suggested normal expression of SMC differentiation markers in KO aortas; however, RNA analyses showed that SMC differentiation markers were increased in KO cardiac outflow vessels but decreased in the descending aorta. KO aortas had only rare mature elastin deposits and contained abnormal aggregates of extracellular matrix proteins. Expression of several matrix proteins was significantly decreased in KO descending aortas but not in cardiac outflow vessels.

Conclusion—

TGF-β signaling in SMCs controls differentiation, matrix synthesis, and vascular morphogenesis. Effects of TGF-β on SMC gene expression appear to differ depending on the location of SMCs in the aorta.
Role of K
ATP
Channels in the Maintenance of Ventricular Fibrillation in Cardiomyopathic Human Hearts
Authors: Farid Talha A. , Nair Krishnakumar , Massé Stephéne , Azam Mohammed Ali , Maguy Ange , Lai Patrick F. H. , Umapathy Karthikeyan , Dorian Paul , Chauhan Vijay , Varró András , Al-Hesayen Abdul , Waxman Menashe , Nattel Stanley , Nanthakumar Kumaraswamy
Published: October 2011

Rationale:

Ventricular fibrillation (VF) leads to global ischemia. The modulation of ischemia-dependent pathways may alter the electrophysiological evolution of VF.

Objective:

We addressed the hypotheses that there is regional disease-related expression of K
ATP
channels in human cardiomyopathic hearts and that K
ATP
channel blockade promotes spontaneous VF termination by attenuating spatiotemporal dispersion of refractoriness.

Methods and Results:

In a human Langendorff model, electric mapping of 6 control and 9 treatment (10 μmol/L glibenclamide) isolated cardiomyopathic hearts was performed. Spontaneous defibrillation was studied and mean VF cycle length was compared regionally at VF onset and after 180 seconds between control and treatment groups. K
ATP
subunit gene expression was compared between LV endocardium versus epicardium in myopathic hearts. Spontaneous VF termination occurred in 1 of 6 control hearts and 7 of 8 glibenclamide-treated hearts (
P
=0.026). After 180 seconds of ischemia, a transmural dispersion in VF cycle length was observed between epicardium and endocardium (
P
=0.001), which was attenuated by glibenclamide. There was greater gene expression of all K
ATP
subunit on the endocardium compared with the epicardium (
P
<0.02). In an ischemic rat heart model, transmural dispersion of refractoriness (ΔERP
Transmural
=ERP
Epicardium
−ERP
Endocardium
) was verified with pacing protocols. ΔERP
Transmural
in control was 5±2 ms and increased to 36±5 ms with ischemia. This effect was greatly attenuated by glibenclamide (ΔERP
Transmural
for glibenclamide+ischemia=4.9±4 ms,
P
=0.019 versus control ischemia).

Conclusions:

K
ATP
channel subunit gene expression is heterogeneously altered in the cardiomyopathic human heart. Blockade of K
ATP
channels promotes spontaneous defibrillation in cardiomyopathic human hearts by attenuating the ischemia-dependent spatiotemporal heterogeneity of refractoriness during early VF.
Epigenetic Regulation of Endothelial Lineage Committed Genes in Pro-Angiogenic Hematopoietic and Endothelial Progenitor Cells
Authors: Ohtani Kisho , Vlachojannis Georgios J. , Koyanagi Masamichi , Boeckel Jes-Niels , Urbich Carmen , Farcas Ruxandra , Bonig Halvard , Marquez Victor E. , Zeiher Andreas M. , Dimmeler Stefanie
Published: October 2011

Rationale:

Proangiogenic hematopoietic and endothelial progenitor cells (EPCs) contribute to postnatal neovascularization, but the mechanisms regulating differentiation to the endothelial lineage are unclear.

Objective:

To elucidate the epigenetic control of endothelial gene expression in proangiogenic cells and EPCs.

Methods and Results:

Here we demonstrate that the endothelial nitric oxide synthase (eNOS) promoter is epigenetically silenced in proangiogenic cells (early EPCs), CD34
+
cells, and mesoangioblasts by DNA methylation and prominent repressive histone H3K27me3 marks. In order to reverse epigenetic silencing to facilitate endothelial commitment, we used 3-deazaneplanocin A, which inhibits the histone methyltransferase enhancer of zest homolog 2 and, thereby, reduces H3K27me3. 3-Deazaneplanocin A was not sufficient to increase eNOS expression, but the combination of 3-deazaneplanocin A and the histone deacetylase inhibitor Trichostatin A augmented eNOS expression, indicating that the concomitant inhibition of silencing histone modification and enhancement of activating histone modification facilitates eNOS expression. In ischemic tissue, hypoxia plays a role in recruiting progenitor cells. Therefore, we examined the effect of hypoxia on epigenetic modifications. Hypoxia modulated the balance of repressive to active histone marks and increased eNOS mRNA expression. The reduction of repressive H3K27me3 was associated with an increase of the histone demethylase Jmjd3. Silencing of Jmjd3 induced apoptosis and senescence in proangiogenic cells and inhibited hypoxia-mediated up-regulation of eNOS expression in mesoangioblasts.

Conclusions:

These findings provide evidence that histone modifications epigenetically control the eNOS promoter in proangiogenic cells.
Intracranial Hemorrhage, Outcome, and Mortality After Intra-Arterial Therapy for Acute Ischemic Stroke in Patients Under Oral Anticoagulants
Authors: De Marchis Gian Marco , Jung Simon , Colucci Giuseppe , Meier Niklaus , Fischer Urs , Weck Anja , Mono Marie-Luise , Galimanis Aekaterini , Mattle Heinrich P. , Schroth Gerhard , Gralla Jan , Arnold Marcel , Brekenfeld Caspar
Published: October 2011

Background and Purpose—

Use of intravenous tissue-type plasminogen activator (IV tPA) for acute ischemic stroke is restricted to patients with an international normalized ratio (INR) less than 1.7. However, a recent study showed increased risk of symptomatic intracranial hemorrhage after IV tPA use in patients with oral anticoagulants (OAC) even with an INR less than 1.7. The present study assessed the risk of symptomatic intracranial hemorrhage, clinical outcome, and mortality after intra-arterial therapy (IAT) in patients with and without previous use of OAC.

Methods—

Consecutive patients treated with IAT from December 1992 to October 2010 were included. Clinical outcome and mortality were assessed 90 days after stroke onset. Patients with and without previous use of OAC were compared.

Results—

Overall, 714 patients were treated with IAT. Twenty-eight patients (3.9%) were under OAC at time of symptom onset. Median INR in the OAC group was 1.79 (interquartile range [IQR], 1.41–2.3) and 1.01 (IQR, 1.0–1.09;
P
<0.0001) in the group without OAC. Patients treated with OAC at admission underwent more often mechanical-only IAT than did patients without OAC (46.4% versus 12.8%;
P
<0.0001). Comparing patients with and without previous use of OAC, we did not find any statistical difference in the rate of symptomatic intracranial hemorrhage (7.1% versus 6.0%;
P
=0.80), unfavorable outcome (modified Rankin Scale score, 3–6; 67.9% versus 50.9%;
P
=0.11), and mortality (17.9% versus 21.6%;
P
=0.58).

Conclusions—

Previous use of OAC did not significantly increase the risk of symptomatic intracranial hemorrhage after IAT or the risk of unfavorable outcome and mortality 90 days after IAT.
Cerebral Blood Flow Is the Optimal CT Perfusion Parameter for Assessing Infarct Core
Authors: Campbell Bruce C.V. , Christensen Søren , Levi Christopher R. , Desmond Patricia M. , Donnan Geoffrey A. , Davis Stephen M. , Parsons Mark W.
Published: October 2011

Background and Purpose—

CT perfusion (CTP) is widely and rapidly accessible for imaging acute ischemic stroke but has limited validation. Cerebral blood volume (CBV) has been proposed as the best predictor of infarct core. We tested CBV against other common CTP parameters using contemporaneous diffusion MRI.

Methods—

Patients with acute ischemic stroke <6 hours after onset had CTP and diffusion MRI <1 hour apart, before any reperfusion therapies. CTP maps of time to peak (TTP), absolute and relative CBV, cerebral blood flow (CBF), mean transit time (MTT), and time to peak of the deconvolved tissue residue function (Tmax) were generated. The diffusion lesion was manually outlined to its maximal visual extent. Receiver operating characteristic (ROC) analysis area under the curve (AUC) was used to quantify the correspondence of each perfusion parameter to the coregistered diffusion-weighted imaging lesion. Optimal thresholds were determined (Youden index).

Results—

In analysis of 98 CTP slabs (54 patients, median onset to CT 190 minutes, median CT to MR 30 minutes), relative CBF performed best (AUC, 0.79; 95% CI, 0.77–81), significantly better than absolute CBV (AUC, 0.74; 95% CI, 0.73–0.76). The optimal threshold was <31% of mean contralateral CBF. Specificity was reduced by low CBF/CBV in noninfarcted white matter in cases with reduced contrast bolus intensity and leukoaraiosis.

Conclusions—

In contrast to previous reports, CBF corresponded with the acute diffusion-weighted imaging lesion better than CBV, although no single threshold avoids detection of false-positive regions in unaffected white matter. This relates to low signal-to-noise ratio in CTP maps and emphasizes the need for optimized acquisition and postprocessing.
Hospitalization Costs for Patients With Acute Ischemic Stroke Treated With Endovascular Embolectomy in the United States
Authors: Brinjikji Waleed , Kallmes David F. , Rabinstein Alejandro A. , Lanzino Giuseppe , Cloft Harry J.
Published: October 2011

Background and Purpose—

It is important to know the costs of hospitalization for patients undergoing endovascular embolectomy so that comparisons can be made with payments to hospitals.

Methods—

Using the National Inpatient Sample, we evaluated the costs of hospitalization for patients treated with endovascular embolectomy in the United States from 2006 to 2008. The primary end point examined in this study was total hospital costs, and these were correlated with clinical outcome.

Results—

A total of 3864 patients received endovascular embolectomy. A total of 1649 patients were <65 years old and 2205 patients were ≥65 years old. Median hospital costs in 2008 dollars were $36 999 (interquartile range, $26 662–$56 405) for patients with good outcome, $50 628 (interquartile range, $33 135–$76 063) for patients with severe disability, and $35 109 (interquartile range, $25 053–$62 621) for patients with mortality.

Conclusions—

Hospitalization costs for patients treated with endovascular embolectomy are rather high, probably due to the serious nature of their illness. Medicare payments have not been adequate reimbursement for these hospitalizations.
Aspirin as a Promising Agent for Decreasing Incidence of Cerebral Aneurysm Rupture
Authors: Hasan David M. , Mahaney Kelly B. , Brown Robert D. , Meissner Irene , Piepgras David G. , Huston John , Capuano Ana W. , Torner James C. ,   for the International Study of Unruptured Intracranial Aneurysms Investigators
Published: October 2011

Background and Purpose—

Chronic inflammation is postulated as an important phenomenon in intracranial aneurysm wall pathophysiology. This study was conducted to determine if aspirin use impacts the occurrence of intracranial aneurysm rupture.

Methods—

Subjects enrolled in the International Study of Unruptured Intracranial Aneurysms (ISUIA) were selected from the prospective untreated cohort (n=1691) in a nested case–control study. Cases were subjects who subsequently had a proven aneurysmal subarachnoid hemorrhage during a 5-year follow-up period. Four control subjects were matched to each case by site and size of aneurysm (58 cases, 213 control subjects). Frequency of aspirin use was determined at baseline interview. Aspirin frequency groups were analyzed for risk of aneurysmal hemorrhage. Bivariable and multivariable analyses were performed using conditional logistic regression.

Results—

A trend of a protective effect for risk of unruptured intracranial aneurysm rupture was observed. Patients who used aspirin 3× weekly to daily had an OR for hemorrhage of 0.40 (95% CI, 0.18–0.87); reference group, no use of aspirin), patients in the “< once a month” group had an OR of 0.80 (95% CI, 0.31–2.05), and patients in the “> once a month to 2×/week” group had an OR of 0.87 (95% CI, 0.27–2.81;
P
=0.025). In multivariable risk factor analyses, patients who used aspirin 3 times weekly to daily had a significantly lower odds of hemorrhage (adjusted OR, 0.27; 95% CI, 0.11–0.67;
P
=0.03) compared with those who never take aspirin.

Conclusions—

Frequent aspirin use may confer a protective effect for risk of intracranial aneurysm rupture. Future investigation in animal models and clinical studies is needed.
Sphingosine Kinase 2 Mediates Cerebral Preconditioning and Protects the Mouse Brain Against Ischemic Injury
Authors: Yung Lai Ming , Wei Ying , Qin Tao , Wang Yumei , Smith Charles D. , Waeber Christian
Published: October 2011

Background and Purpose—

Cerebral preconditioning provides insights into endogenous mechanisms that protect the brain from ischemic injury. Hypoxia and the anesthetic isoflurane are powerful preconditioning agents. Recent data show that sphingosine 1-phosphate receptor stimulation improves outcome in rodent models of stroke. Endogenous sphingosine 1-phosphate levels are controlled by the expression and activity of sphingosine kinases (SPK). We hypothesize that SPK upregulation mediates preconditioning induced by isoflurane and hypoxia and reduces ischemic injury.

Methods—

Male wild-type C57BL/J, SPK1
−/−
and SPK2
−/−
mice were exposed to isoflurane or hypoxia preconditioning before transient middle cerebral artery occlusion. Infarct volume and neurological outcome were measured 24 hours later. SPK inhibitors (SKI-II and ABC294640) were used to test the involvement of SPK2. Expressions of SPK1, SPK2, and hypoxia-inducible factor 1α were determined. Primary cultures of mouse cortical neurons were exposed to isoflurane before glutamate- or hydrogen peroxide-induced cell death.

Results—

Isoflurane preconditioning and hypoxia preconditioning significantly reduced infarct volume and improved neurological outcome in wild-type and SPK1
−/−
mice but not in SPK2
−/−
mice. Pretreatment with SKI-II or ABC294640 abolished the isoflurane preconditioning-induced tolerance. Western blot showed a rapid and sustained increase in SPK2 level, whereas SPK1 level was similar between preconditioned mice and controls. Hypoxia-inducible factor 1α was upregulated in wild-type isoflurane-preconditioned mice but not in SPK2
−/−
. Isoflurane preconditioning protected primary neurons against cell death, which was abolished in ABC294640-treated cells.

Conclusions—

Applying genetic and pharmacological approaches, we demonstrate that neuronal SPK2 isoform plays an important role in cerebral preconditioning.