bluuebunny/crossref_metadata_2025 huggingface dataset:
Hepatic myelopathy: an unusual neurological complication of chronic liver disease presenting as quadriparesis
Authors: Kori Prakash , Sahu Ritesh , Jaiswal Anupam , Shukla Rakesh
Published: June 2013

Hepatic myelopathy is a rare neurological complication of chronic liver disease, which is usually seen in adults, presenting as pure motor spastic paraparesis. It is almost always associated with portosystemic shunts and hepatic decompensation. We report a rare case of a young adult man presenting as rapidly progressive spastic quadriparesis because of hepatic myelopathy and associated spontaneous splenorenal shunt and early hepatic decompensation.
Personhood within the context of sedation at the end of life in Singapore
Authors: Radha Krishna Lalit Kumar
Published: June 2013

The concept of personhood is critical to the provision of holistic, patient-centred, palliative care yet no common definition of this term exists. Some characterise personhood by the presence of consciousness-related features such as self-awareness while others deem personhood present by virtue of Divine endowment or as a result of one's social relations. Efforts to appropriately delineate this concept come under scrutiny following suggestions that patients rendered deeply and irreversibly unconscious lack personhood and ought to be considered ‘dead’.

This case report studies the views of a family caring for a deeply sedated terminally ill patient, to appropriately site local views of personhood within the context of sedation at the end of life. The resultant Ring Theory of Personhood dispenses with concerns that personhood is solely dependent upon consciousness and distances sedative treatments of last resort such as continuous deep sedation from euthanasia.
Poor outcome associated with probable bilateral extracranial ICA vasospasm
Authors: Sawa Nobufusa Nobuhiro , Kataoka Hiroshi , Ueno Satoshi
Published: June 2013

We describe a woman with bilateral extracranial internal carotid artery (ICA) vasospasm. Initial MRI of the brain showed multiple areas of high-signal intensity in the white matter of both the frontoparietal lobes. She was alert, and the muscle strength of the four extremities was moderately decreased. Cranial CT on day 3 showed increased numbers of low-density areas in both the anterior cerebral arteries (ACA) and middle cerebral arteries (MCA), accompanied by neurological deterioration. Cranial and cervical CT angiography on day 9 showed that all areas of both the ACA and MCA had become low density. Both ICAs were markedly narrowed along their entire length and tapered. On day 16, the patient died. Three patients with bilateral extracranial ICA spasms have been described previously. To our knowledge, this is the first time to document bilateral ICA spasm causing elongated narrowing of the carotid arteries, leading to an unfortunate outcome.
L-2 Hydroxyglutaric aciduria presenting with status epilepticus
Authors: Işikay Sedat
Published: June 2013

L-2 Hydroxyglutaric aciduria is a rare, progressive, autosomal recessively inherited metabolic disorder of organic acid metabolism. It is characterised by macrocephaly, progressive neurological syndrome with cerebellar features, mental deterioration, typical brain MRI findings and the presence of L-2 hydroxyglutaric acid in urine samples. We report on an 11-year-old patient who presented to the emergency department with a generalised status epilepticus, which was subsequently diagnosed as L-2 hydroxyglutaric aciduria owing to rare and different clinical presentation. Brain MRI showed peripheral white matter abnormalities in cerebral hemispheres, basal ganglia and dentate nuclei, In conclusion, L-2 hydroxyglutaric aciduria should be considered in cases of epileptic seizures such as status epilepticus, cerebellar signs and progressive neurological course.
Impact from point-of-care devices on emergency department patient processing times compared with central laboratory testing of blood samples: a randomised controlled trial and cost-effectiveness analysis
Authors: Asha Stephen Edward , Chan Adam Chiu Fat , Walter Elizabeth , Kelly Patrick J , Morton Rachael L , Ajami Allan , Wilson Roger Denis , Honneyman Daniel
Published: June 2013

Objective

To determine if time to disposition decisions for emergency department (ED) patients can be reduced when blood tests are processed using point-of-care (POC) devices and to conduct a cost-effectiveness analysis of POC compared with laboratory testing.

Methods

This randomised trial enrolled adults suspected of an acute coronary syndrome or presenting with conditions considered to only require blood tests available by POC. Participants were randomised to have blood tests processed by POC or laboratory. Outcomes measured were time to disposition decision and ED length-of-stay (LOS). The cost-effectiveness analysis calculated the total and mean costs per ED presentation, as well as total and mean benefits in time saved to disposition decision.

Results

There were 410 POC participants and 401 controls. The mean times to a disposition decision for POC versus controls were 3.24 and 3.50 h respectively, a difference of 7.6% (95% CI 0.4% to 14.3%, p=0.04), and 4.32 and 4.52 h respectively for ED LOS, a difference of 4.4% (95% CI −2.7% to 11.0%, p=0.21). Improved processing time was greatest for participants enrolled by senior staff with a reduction in time to disposition decision of 19.1% (95% CI 7.3% to 29.4%, p<0.01) and ED LOS of 15.6% (95% CI 4.9% to 25.2%, p=0.01). Mean pathology costs were $12 higher in the POC group (95% CI $7 to $18) and the incremental cost-effectiveness ratio was $113 per hour saved in time to disposition decision for POC compared with standard laboratory testing.

Conclusions

Small improvements in disposition decision time were achieved with POC testing for a moderate increase in cost. Greatest benefit may be achieved when POC is targeted to senior medical staff.
Temporary Solitaire stent neck remodeling in the coiling of ruptured aneurysms
Authors: Almekhlafi Mohammed A , Hockley Aaron , Wong John H , Goyal Mayank
Published: June 2013

Background

Stent-assisted coiling is a commonly adopted technique employed in the coiling of broader-based aneurysms. It avoids flow arrest and the risk of vessel rupture associated with balloon-assisted coiling. However, there is a risk of stent thrombosis with the corollary risk of stroke during and after the procedure. Antiplatelet agents are used to mitigate this risk but raise a secondary concern of hemorrhagic complications, particularly with ruptured aneurysm where further interventions such as ventriculostomy occur not infrequently. Stent removal after coil embolization would eliminate the risk of post-procedure stent thromboembolic complications and alleviate the need for continuing antiplatelet therapy.

Methods

A prospectively maintained endovascular database was searched to identify patients who underwent stent-assisted coil embolization followed by stent retrieval and removal. The clinical and technical aspects of the cases were obtained in addition to the procedural outcomes.

Results

Three cases were identified where the use of the fully resheathable Solitaire AB Neurovascular Remodeling Device permitted the coiling of broad-based aneurysms with subsequent retrieval and removal of the stent. All patients presented with subarachnoid hemorrhage and received aspirin prior to the procedure. Two patients did not require antiplatelet therapy after the procedure. No coil herniation or thromboembolic events were encountered.

Conclusions

Stent retrieval and removal can be done safely in selected cases at the end of stent-assisted coil embolization using the Solitaire AB device. This technique avoids the need for continuing antiplatelet therapy, which can be particularly important in the setting of acute subarachnoid hemorrhage.
Transcription Regulation at the Core: Similarities Among Bacterial, Archaeal, and Eukaryotic RNA Polymerases
Authors: Decker Kimberly B. , Hinton Deborah M.
Published: June 2013

Multisubunit RNA polymerases are complex protein machines that require a specificity factor for the recognition of a specific transcription start site. Although bacterial σ factors are thought to be quite different from the specificity factors employed in higher organisms, a comparison of the σ/RNA polymerase structures with recent structures of eukaryotic Pol II together with TFIIB highlights significant functional similarities. Other work reveals that both bacterial and eukaryotic promoters are composed of modular elements that are used in different combinations. Bacteria, archaea, and eukaryotes also utilize similar strategies to alter core promoter specificity, from specificity factor exchange to the employment of activators that bind close to or overlap core promoter sequences, directing the transcriptional machinery to a new start site. Here we examine the details of core promoter recognition in bacteria that reveal the transcriptional similarities throughout biology.
Application of Electrochemical Impedance Spectroscopy in Characterization of Mass- and Charge Transfer Processes in Dye-Sensitized Solar Cells
Authors: Nguyen Thai Hoang , Tran Hai MInh , Nguyen Thi Phuong Thoa
Published: June 2013

Electrochemical impedance spectroscopy (EIS) technique was performed to study electronic and ionic processes in dye-sensitized solar cells (DSCs), and consequently, to evaluate the dye degradation mechanism. DSCs based on nano crystalline titanium dioxide (TiO2) sensitized by N719 dye and a liquid electrolyte system, were assembled. The fabrication of cell components such as anode and cathode, and cell assembling were studied and improved. By analyzing the impedance data, the electron transport rate, electron lifetime in the mesoscopic TiO2 film and parameters of ionic diffusion process in the electrolyte, have been derived. The fabricated DSCs were treated with 4-tert-butylpyridine and nicotinic acid by injection technique. The effect of 4-tert-butylperidine and nicotinic acid on the DSC performance has been interpreted by analysis of impedance data. The degradation of DSC performance under prolonged thermal ageing and light soaking was found to be correlated with the decrease of both diffusion rate of electron in the TiO2 film and diffusion rate of ions in the electrolyte. The degradation rate of DSC performance parameters under light soaking was higher than under thermal ageing. 4-TBP-treated DSCs show high performance just after fabrication but rapidly degraded during light ageing and thermal stress. Nicotinic acid treatment slowed the thermal degradation of DSCs in the dark.
Study of the Copper Electrodeposition Mechanism on Molybdenum Substrate
Authors: Delbos Elise , El Belghiti Hanane , Mercier Dimitri , Vigneron Jackie , Bouttemy Muriel , Etcheberry Arnaud
Published: June 2013

Molybdenum substrates are mainly used for photovoltaic applications, and specifically as support for absorber deposition, for thin film solar cells. For these applications, one of the technologic key points is the electrodeposition of a copper layer. Furthermore, in the microelectronic domain, OMG Ultra Pure Chemicals (UPC) has developed a specific chemistry (OMniCuTM chemistry), enhanced by organic additives, dedicated to the copper electrodeposition on copper substrates (Damascene and Through Silicon Vias applications) (1,2). The aim of this article is to determine the efficiency of this commercial chemistry to coat a homogeneous, uniform, hiding and adherent copper layer on molybdenum substrates, with a monitoring thickness, lower than 100nm.
Nicotine potentiates proatherogenic effects of oxLDL by stimulating and upregulating macrophage CD36 signaling
Authors: Zhou Ming-Sheng , Chadipiralla Kiranmai , Mendez Armando J. , Jaimes Edgar A. , Silverstein Roy L. , Webster Keith , Raij Leopoldo
Published: June 2013

Cigarette smoking is a major risk factor for atherosclerosis and cardiovascular disease. CD36 mediates oxidized LDL (oxLDL) uptake and contributes to macrophage foam cell formation. We investigated a role for the CD36 pathway in nicotine-induced activation of macrophages and foam cell formation in vitro and in vivo. Nicotine in the same plasma concentration range found in smokers increased the CD36+/CD14+cell population in human peripheral blood mononuclear cells, increased CD36 expression of human THP1 macrophages, and increased macrophage production of reactive oxygen species, PKCδ phosphorylation, and peroxisome proliferator-activated receptor-γ (PPARγ) expression. Nicotine-induced CD36 expression was suppressed by antioxidants and by specific PKCδ and PPARγ inhibitors, implicating mechanistic roles for these intermediates. Nicotine synergized with oxLDL to increase macrophage expression of CD36 and cytokines TNF-α, monocyte chemoattractant protein-1, IL-6, and CXCL9, all of which were prevented by CD36 small interfering (si)RNA. Incubation with oxLDL (50 μg/ml) for 72 h resulted in lipid deposition in macrophages and foam cell formation. Preincubation with nicotine further increased oxLDL-induced lipid accumulation and foam cell formation, which was also prevented by CD36 siRNA. Treatment of apoE−/−mice with nicotine markedly exacerbated inflammatory monocyte levels and atherosclerotic plaque accumulation, effects that were not seen in CD36−/−apoE−/−mice. Our results show that physiological levels of nicotine increase CD36 expression in macrophages, a pathway that may account at least in part for the known proinflammatory and proatherogenic properties of nicotine. These results identify such enhanced CD36 expression as a novel nicotine-mediated pathway that may constitute an independent risk factor for atherosclerosis in smokers. The results also suggest that exacerbated atherogenesis by this pathway may be an adverse side effect of extended use of high concentrations of nicotine independent of their mode of administration.
Platelet-derived growth factor-A and sonic hedgehog signaling direct lung fibroblast precursors during alveolar septal formation
Authors: McGowan Stephen E. , McCoy Diann M.
Published: June 2013

Alveolar septal formation is required to support the respiration of growing mammals; in humans effacement of the alveolar surface and impaired gas exchange are critical features of emphysema and pulmonary fibrosis. Platelet-derived growth factor-A (PDGF-A) and its receptor PDGF-receptor-α (PDGFRα) are required for secondary septal elongation in mice during postnatal days 4 through 12 and they regulate the proliferation and septal location of interstitial fibroblasts. We examined lung fibroblasts (LF) to learn whether PDGFRα expression distinguished a population of precursor cells, with enhanced proliferative and migratory capabilities. We identified a subpopulation of LF that expresses sonic hedgehog (Shh) and stem cell antigen-1 (Sca1). PDGF-A and Shh both increased cytokinesis and chemotaxis in vitro, but through different mechanisms. In primary LF cultures, Shh signaled exclusively through a noncanonical pathway involving generation of Rac1-GTP, whereas both the canonical and noncanonical pathways were used by the Mlg neonatal mouse LF cell line. LF preferentially oriented their primary cilia toward their anterior pole during migration. Furthermore, a larger proportion of PDGFRα-expressing LF, which are more abundant at the septal tips, bore primary cilia compared with other alveolar cells. In pulmonary emphysema, destroyed alveolar septa do not regenerate, in part because cells fail to assume a configuration that allows efficient gas exchange. Better understanding how LF are positioned during alveolar development could identify signaling pathways, which promote alveolar septal regeneration.
Neonatal hyperoxia alters the host response to influenza A virus infection in adult mice through multiple pathways
Authors: Buczynski Bradley W. , Yee Min , Martin Kyle C. , Lawrence B. Paige , O'Reilly Michael A.
Published: June 2013

Exposing preterm infants or newborn mice to high concentrations of oxygen disrupts lung development and alters the response to respiratory viral infections later in life. Superoxide dismutase (SOD) has been separately shown to mitigate hyperoxia-mediated changes in lung development and attenuate virus-mediated lung inflammation. However, its potential to protect adult mice exposed to hyperoxia as neonates against viral infection is not known. Here, transgenic mice overexpressing extracellular (EC)-SOD in alveolar type II epithelial cells are used to test whether SOD can alleviate the deviant pulmonary response to influenza virus infection in adult mice exposed to hyperoxia as neonates. Fibrotic lung disease, observed following infection in wild-type (WT) mice exposed to hyperoxia as neonates, was prevented by overexpression of EC-SOD. However, leukocyte recruitment remained excessive, and levels of monocyte chemoattractant protein (MCP)-1 remained modestly elevated following infection in EC-SOD Tg mice exposed to hyperoxia as neonates. Because MCP-1 is often associated with pulmonary inflammation and fibrosis, the host response to infection was concurrently evaluated in adult Mcp-1 WT and Mcp-1 knockout mice exposed to neonatal hyperoxia. In contrast to EC-SOD, excessive leukocyte recruitment, but not lung fibrosis, was dependent upon MCP-1. Our findings demonstrate that neonatal hyperoxia alters the inflammatory and fibrotic responses to influenza A virus infection through different pathways. Therefore, these data suggest that multiple therapeutic strategies may be needed to provide complete protection against diseases attributed to prematurity and early life exposure to oxygen.
Falkner-Skan Flow of a Maxwell Fluid with Heat Transfer and Magnetic Field
Authors: Qasim M. , Noreen S.
Published: June 2013

This investigation deals with the Falkner-Skan flow of a Maxwell fluid in the presence of nonuniform applied magnetic field with heat transfer. Governing problems of flow and heat transfer are solved analytically by employing the homotopy analysis method (HAM). Effects of the involved parameters, namely, the Deborah number, Hartman number, and the Prandtl number, are examined carefully. A comparative study is made with the known numerical solution in a limiting sense and an excellent agreement is noted.
Continuing Medical Education for Primary Care Physicians in Israel: A Cross-Sectional Study
Authors: Shvartzman Pesach , Tandeter Howard , Vardy Daniel , Matz Eran , Heymann Anthony , Peleg Roni
Published: June 2013

Acquiring a medical degree is only the beginning of a prolonged learning process. At some point, formal studies end, and continuing medical education (CME) may be left to personal initiative. To assess lifetime learning (LL) and CME among primary care physicians in Israel, a self-administered questionnaire, based on the Jefferson Scale of Physician Lifelong Learning (JSPLL), was mailed to 4,104 primary care physicians. A total of 979 completed the study, 53.4% males with a mean age of 51.8 ± 8.3 (range 31–79). A logistic regression model showed that male gender (OR = 1.5, P<0.05), teaching (OR = 4.5, P<0.0001), and not working in a rural clinic (OR = 0.6, P<0.01), increased the LL score. The results of the study demonstrate a need to address special subgroups that have a lower tendency to engage in LL activities. Policymakers should develop strategies to increase these physicians' interest in LL activities and the accessibility of these activities to them, including the availability of LL resources at home so physicians can get updates at their convenience. Primary care physicians should also be encouraged to become involved in teaching of any type, as this is a facilitating factor for LL activities.
Vaccine-Instructed Intratumoral IFN-γ Enables Regression of Autochthonous Mouse Prostate Cancer in Allogeneic T-Cell Transplantation
Authors: Hess Michelini Rodrigo , Manzo Teresa , Sturmheit Tabea , Basso Veronica , Rocchi Martina , Freschi Massimo , Listopad Joanna , Blankenstein Thomas , Bellone Matteo , Mondino Anna
Published: June 2013

Vaccination can synergize with transplantation of allogeneic hematopoietic stem cells to cure hematologic malignancies, but the basis for this synergy is not understood to the degree where such approaches could be effective for treating solid tumors. We investigated this issue in a transgenic mouse model of prostate cancer treated by transplantation of a nonmyeloablative MHC-matched, single Y chromosome–encoded, or multiple minor histocompatibility antigen-mismatched hematopoietic cell preparation. Here, we report that tumor-directed vaccination after allogeneic hematopoietic stem cell transplantation and donor lymphocyte infusion is essential for acute graft versus tumor responses, tumor regression, and prolonged survival. Vaccination proved essential for generation of CD8+ IFN-γ+ tumor-directed effector cells in secondary lymphoid organs and also for IFN-γ+ upregulation at the tumor site, which in turn instructed local expression of proinflammatory chemokines and intratumoral recruitment of donor-derived T cells for disease regression. Omitting vaccination, transplanting IFN-γ–deficient donor T cells, or depleting alloreactive T cells all compromised intratumoral IFN-γ–driven inflammation and lymphocyte infiltration, abolishing antitumor responses and therapeutic efficacy of the combined approach. Our findings argue that posttransplant tumor-directed vaccination is critical to effectively direct donor T cells to the tumor site in cooperation with allogeneic hematopoietic cell transplantation. Cancer Res; 73(00); 4641–52. ©2013 AACR.
Proteomic and Lipidomic Signatures of Lipid Metabolism in NASH-Associated Hepatocellular Carcinoma
Authors: Muir Kyle , Hazim Antonious , He Ying , Peyressatre Marion , Kim Do-Young , Song Xiaoling , Beretta Laura
Published: June 2013

Nonalcoholic steatohepatitis (NASH) is a common preneoplastic condition of hepatocellular carcinoma (HCC). Mice with hepatocytic deletion of Pten develop NASH and HCC later in life. This model is highly valuable for studies aimed at identifying the molecular mechanism by which metabolic disorders contribute to tumor development. We applied proteomic and lipidomic profiling approaches to Pten-null NASH liver and tumors. Circulating fatty acid composition was also characterized in these mice. The relevance to human NASH and HCC was further validated. This integrative proteomic and lipidomic study from mouse to human and from liver to blood identified the following disease signatures: (i) an HCC signature: upregulated hepatic scd1/scd2, fads2, and acsl5:acsl1 ratio, elevated vaccenic and erucic acids, and reduced margaric and linoleic acids in both liver and plasma; (ii) a NASH signature that correlates with tumor burden: upregulated hepatic elovl6, elevated oleic, adrenic, and osbond acids, and reduced cervonic acid in liver and plasma; and (iii) a NASH signature: reduced hepatic and circulating lignoceric and eicosapentaenoic acids. Altogether, these results show the role of lipid-modifying enzymes converting saturated fatty acids (SFA) to monounsaturated fatty acids (MUFA) in HCC and the importance of an increased ratio of long chain n6-polyunsaturated fatty acids over n3-polyunsaturated fatty acids in NASH and HCC risk. They also highlight the relevance of the Pten-null model for studies related to NASH and HCC and show that circulating lipid metabolome provides a direct read of lipid changes in the liver. Most importantly, novel candidate targets for HCC diagnosis, therapy, risk assessment, and prevention were identified. Cancer Res; 73(15); 4722–31. ©2013 AACR.
Peroxiredoxin-2 Represses Melanoma Metastasis by Increasing E-Cadherin/β-Catenin Complexes in Adherens Junctions
Authors: Lee Doo Jae , Kang Dong Hoon , Choi Mina , Choi Yang Ji , Lee Joo Young , Park Joo Hyun , Park Yoon Jung , Lee Kyung Wha , Kang Sang Won
Published: June 2013

In melanoma, transition to the vertical growth phase is the critical step in conversion to a deadly malignant disease. Here, we offer the first evidence that an antioxidant enzyme has a key role in this transition. We found that the antioxidant enzyme peroxiredoxin-2 (Prx2) inversely correlated with the metastatic capacity of human melanoma cells. Silencing Prx2 expression stimulated proliferation and migration, whereas ectopic expression of Prx2 produced the opposite effect. Mechanistic investigations indicated that Prx2 negatively regulated Src/ERK activation status, which in turn fortified adherens junctions function by increasing E-cadherin expression and phospho-Y654–dependent retention of β-catenin in the plasma membrane. In murine melanoma cells, Prx2 silencing enhanced lung metastasis in vivo. Interestingly, the natural compound gliotoxin, which is known to exert a Prx-like activity, inhibited proliferation and migration as well as lung metastasis of Prx2-deficient melanoma cells. Overall, our findings reveal that Prx2 is a key regulator of invasion and metastasis in melanoma, and also suggest a pharmacologic strategy to effectively decrease deadly malignant forms of this disease. Cancer Res; 73(15); 4744–57. ©2013 AACR.
Intravital FLIM-FRET Imaging Reveals Dasatinib-Induced Spatial Control of Src in Pancreatic Cancer
Authors: Nobis Max , McGhee Ewan J. , Morton Jennifer P. , Schwarz Juliane P. , Karim Saadia A. , Quinn Jean , Edward Mike , Campbell Andrew D. , McGarry Lynn C. , Evans T.R. Jeffry , Brunton Valerie G. , Frame Margaret C. , Carragher Neil O. , Wang Yingxiao , Sansom Owen J. , Timpson Paul , Anderson Kurt I.
Published: June 2013

Cancer invasion and metastasis occur in a complex three-dimensional (3D) environment, with reciprocal feedback from the surrounding host tissue and vasculature-governing behavior. In this study, we used a novel intravital method that revealed spatiotemporal regulation of Src activity in response to the anti-invasive Src inhibitor dasatinib. A fluorescence lifetime imaging microscopy–fluorescence resonance energy transfer (FLIM-FRET) Src biosensor was used to monitor drug-targeting efficacy in a transgenic p53-mutant mouse model of pancreatic cancer. In contrast to conventional techniques, FLIM-FRET analysis allowed for accurate, time-dependent, live monitoring of drug efficacy and clearance in live tumors. In 3D organotypic cultures, we showed that a spatially distinct gradient of Src activity exists within invading tumor cells, governed by the depth of penetration into complex matrices. In parallel, this gradient was also found to exist within live tumors, where Src activity is enhanced at the invasive border relative to the tumor cortex. Upon treatment with dasatinib, we observed a switch in activity at the invasive borders, correlating with impaired metastatic capacity in vivo. Src regulation was governed by the proximity of cells to the host vasculature, as cells distal to the vasculature were regulated differentially in response to drug treatment compared with cells proximal to the vasculature. Overall, our results in live tumors revealed that a threshold of drug penetrance exists in vivo and that this can be used to map areas of poor drug-targeting efficiency within specific tumor microenvironments. We propose that using FLIM-FRET in this capacity could provide a useful preclinical tool in animal models before clinical translation. Cancer Res; 73(15); 4674–86. ©2013 AACR.
PanIN-Specific Regulation of Wnt Signaling by HIF2α during Early Pancreatic Tumorigenesis
Authors: Criscimanna Angela , Duan Li-Juan , Rhodes Julie A. , Fendrich Volker , Wickline Emily , Hartman Douglas J. , Monga Satdarshan P.S. , Lotze Michael T. , Gittes George K. , Fong Guo-Hua , Esni Farzad
Published: June 2013

Hypoxia promotes angiogenesis, proliferation, invasion, and metastasis of pancreatic cancer. Essentially, all studies of the hypoxia pathway in pancreatic cancer research to date have focused on fully malignant tumors or cancer cell lines, but the potential role of hypoxia inducible factors (HIF) in the progression of premalignant lesions has not been critically examined. Here, we show that HIF2α is expressed early in pancreatic lesions both in human and in a mouse model of pancreatic cancer. HIF2α is a potent oncogenic stimulus, but its role in Kras-induced pancreatic neoplasia has not been discerned. We used the Ptf1aCre transgene to activate KrasG12D and delete Hif2α solely within the pancreas. Surprisingly, loss of Hif2α in this model led to markedly higher, rather than reduced, number of low-grade pancreatic intraepithelial neoplasia (mPanIN) lesions. These lesions, however, failed to progress to high-grade mPanINs, and displayed exclusive loss of β-catenin and SMAD4. The relationship among HIF2α, β-catenin, and Smad4 was further confirmed in vitro, where silencing of Hif2α resulted in reduced β-catenin and Smad4 transcript levels. Thus, with oncogenic Ras expressed in the pancreas, HIF2α modulates Wnt-signaling during mPanIN progression by maintaining appropriate levels of both Smad4 and β-catenin. Cancer Res; 73(15); 4781–90. ©2013 AACR.
Enhanced Radiation Sensitivity in HPV-Positive Head and Neck Cancer
Authors: Kimple Randall J. , Smith Molly A. , Blitzer Grace C. , Torres Alexandra D. , Martin Joshua A. , Yang Robert Z. , Peet Chimera R. , Lorenz Laurel D. , Nickel Kwangok P. , Klingelhutz Aloysius J. , Lambert Paul F. , Harari Paul M.
Published: June 2013

Patients with human papillomavirus (HPV+)–associated head and neck cancer (HNC) show significantly improved survival outcome compared with those with HPV-negative (HPV−) tumors. Published data examining this difference offers conflicting results to date. We systematically investigated the radiation sensitivity of all available validated HPV+ HNC cell lines and a series of HPV− HNC cell lines using in vitro and in vivo techniques. HPV+ HNCs exhibited greater intrinsic radiation sensitivity (average SF2 HPV−: 0.59 vs. HPV+: 0.22; P < 0.0001), corresponding with a prolonged G2–M cell-cycle arrest and increased apoptosis following radiation exposure (percent change 0% vs. 85%; P = 0.002). A genome-wide microarray was used to compare gene expression 24 hours following radiation between HPV+ and HPV− cell lines. Multiple genes in TP53 pathway were upregulated in HPV+ cells (Z score 4.90), including a 4.6-fold increase in TP53 (P < 0.0001). Using immortalized human tonsillar epithelial (HTE) cells, increased radiation sensitivity was seen in cell expressing HPV-16 E6 despite the effect of E6 to degrade p53. This suggested that low levels of normally functioning p53 in HPV+ HNC cells could be activated by radiation, leading to cell death. Consistent with this, more complete knockdown of TP53 by siRNA resulted in radiation resistance. These results provide clear evidence, and a supporting mechanism, for increased radiation sensitivity in HPV+ HNC relative to HPV− HNC. This issue is under active investigation in a series of clinical trials attempting to de-escalate radiation (and chemotherapy) in selected patients with HPV+ HNC in light of their favorable overall survival outcome. Cancer Res; 73(15); 4791–800. ©2013 AACR.
Parkinson's Disease Genes Do Not Segregate with Breast Cancer Genes' Loci
Authors: Kravitz Efrat , Laitman Yael , Hassin-Baer Sharon , Inzelberg Rivka , Friedman Eitan
Published: June 2013

Background: Breast cancer and skin cancer rates among patients with Parkinson's disease are higher than in non-Parkinson's disease cases, and Jewish-Ashkenazi LRRK2*G2019S mutation carriers have higher breast cancer rates than noncarriers. Because additional Parkinson's disease predisposition genes are implicated in the malignant transformation process, we hypothesized that the association between breast cancer and Parkinson's disease may be related to segregation of breast cancer loci with known Parkinson's disease predisposition loci.

Methods: Data mining for single-nucleotide polymorphisms (SNP), reportedly associated with breast cancer in genome-wide association study (GWAS) that localize to chromosomes bearing known Parkinson's disease predisposition loci: PARK7, PINK1 (chromosome 1); SNCA (chromosome 4); PARK2 (chromosome 6); and LRRK2 (chromosome 12), was carried out.

Results: A total of 188 breast cancer–associated SNPs were identified in 29 eligible manuscripts: 43 SNPs on chromosome 1 (PINK1), 46 SNPs on chromosome 4 (SNCA), 72 SNPs on chromosome 6 (PARK2), and 27 SNPs on chromosome 12 (LRRK2). No breast cancer–associated SNP was located at distance less than 500,000 bp from any of the analyzed Parkinson's disease predisposition genes.

Conclusions: The association between breast cancer and the most common genetic-inherited forms of Parkinson's disease cannot be accounted for by allele cosegregation at the genomic level.

Impact: To elucidate the association between Parkinson's disease and breast cancer, a comprehensive approach that spans beyond a simple genetic association is required. Cancer Epidemiol Biomarkers Prev; 22(8); 1464–72. ©2013 AACR.
Limited Role of the Receptor for Advanced Glycation End Products during Streptococcus pneumoniae Bacteremia
Authors: Achouiti Ahmed , de Vos Alex F. , de Beer Regina , Florquin Sandrine , van 't Veer Cornelis , van der Poll Tom
Published: June 2013

Streptococcus pneumoniae is one of the most common causes of sepsis. Sepsis is associated with the release of 'damage-associated molecular patterns' (DAMPs). The receptor for advanced glycation end products (RAGE) is a multiligand receptor, abundantly expressed in the lungs, that recognizes several of these DAMPs. Triggering of RAGE leads to activation of the NF-κB pathway and perpetuation of inflammation. Earlier investigations have shown that the absence of RAGE reduces inflammation and bacterial dissemination and increases survival in sepsis caused by S. pneumoniae pneumonia. We hypothesized that the detrimental role of RAGE depends on the level of RAGE expression in the primary organ of infection. By directly injecting S. pneumoniae intravenously, thereby circumventing the extensive RAGE-expressing lung, we here determined whether RAGE contributes to an adverse outcome of bacteremia or whether its role is restricted to primary lung infection. During late-stage infection (48 h), rage-/- mice had an attenuated systemic inflammatory response, as reflected by lower plasma levels of proinflammatory cytokines, reduced endothelial cell activation (as measured by E-selectin levels) and less neutrophil accumulation in lung tissue. However, RAGE deficiency did not influence bacterial loads or survival in this model. In accordance, plasma markers for cell injury were similar in both mouse strains. These results demonstrate that while RAGE plays a harmful part in S. pneumoniae sepsis originating from the respiratory tract, this receptor has a limited role in the outcome of primary bloodstream infection by this pathogen.
Allopregnanolone Promotes Success in Food Competition in Subordinate Male Rats
Authors: Löfgren Magnus , Bengtsson Sara K. , Johansson Maja , Bäckström Torbjörn
Published: June 2013

Background/Aims: Allopregnanolone or 3α-hydroxy-5α-pregnan-20-one (AlloP) is normally sedative and anxiolytic, but can under provoking circumstances paradoxically induce aggressive behavior. Therefore, it is of particular interest to determine if there is a relationship between an anxiolytic effect and aggressive behavior following AlloP administration. Method: Male Wistar rats were housed in triads comprising of 1 young rat (35 days) and 2 older rats (55 days), with the intent of producing a social hierarchy. The triads were sampled for total serum testosterone and submitted to a social challenge in the form of a food competition test (FCT), where the rats competed for access to drinking sweetened milk. At baseline, the younger rats were identified as subordinates. To test for the behavioral effect of AlloP, the subordinate rats were given intravenous AlloP injections of 0.5 and 1 mg/kg. To assess the optimal AlloP effect, 6 intervals (5, 10, 15, 20, 30 and 40 min) between injection and the FCT were used. In separate studies, AlloP was also given by subcutaneous and intraperitoneal administration at 10 and 17 mg/kg. Results: AlloP (1 mg/kg, i.v.) increased drinking time and aggressive behavior in subordinate rats, with a positive correlation between these behaviors. The subcutaneous injection (17 mg/kg) also increased drinking time in subordinate animals. Serum testosterone concentration was higher in dominant compared to subordinate rats, and correlated with drinking time and weight. Conclusions: AlloP increased drinking time and aggressive behavior, and the correlation indicates a relationship between an anxiolytic effect and aggressive behavior.
Cyclosporine Attenuates Arginine Transport, in Human Endothelial Cells, through Modulation of Cationic Amino Acid Transporter-1
Authors: Grupper Ayelet , Shashar Moshe , Bahry Dganit , Pri-Paz Yael , Tur Ohad Ben , Levi Sharon , Chernichovski Tamara , Chernin Gil , Schwartz Idit F.
Published: June 2013

Background: The spectrum of cardiovascular toxicity by cyclosporine (CsA) includes hypertension, accelerated atherosclerosis, and thrombotic microangiopathy, all of which are the result of endothelial cell dysfunction. Endothelial cell dysfunction is characterized by decreased endothelial nitric oxide synthase (eNOS) activity. Cationic amino acid transporter-1 (CAT-1) is the specific arginine transporter for eNOS. CsA has been shown to attenuate nitric oxide (NO) generation. However, the mechanism remains elusive. We hypothesize that CsA inhibits eNOS activity through modulation of its selective arginine supplier CAT-1. Methods: We studied the effect of CsA on arginine uptake, NO2/NO3 generation, and CAT-1, protein kinase Cα (PKCα), and phosphorylated PKCα protein expression in human umbilical vein endothelial cell cultures (HUVEC) in the absence and presence of L-arginine. Results: CsA (0.5-2 μg/ml) significantly attenuated arginine transport in a dose- and time-dependent manner, a phenomenon which was prevented by co-incubation with L-arginine (1 mM). The aforementioned findings were accompanied by increased protein nitration, a measure for peroxynitrite accumulation. In contrast, no changes were observed in NO2/NO3 generation. CsA significantly decreased the abundance of CAT-1 protein, an effect that was attenuated by L-arginine. PKCα and phosphorylated PKCα (CAT-1 inhibitors) protein contents were not affected by CsA. Conclusion: CsA inhibits arginine transport and induces protein nitration in HUVEC through modulation of CAT-1.
Patients Suffering from Restless Legs Syndrome Have Low Internal Locus of Control and Poor Psychological Functioning Compared to Healthy Controls
Authors: Brand Serge , Beck Johannes , Hatzinger Martin , Holsboer-Trachsler Edith
Published: June 2013

Background: Restless legs syndrome (RLS) is a disturbing sensorimotor disorder negatively influencing both sleep and psychological functioning. The aim of the present study was to assess RLS patients with respect to locus of control, sleep-related personality traits, quality of life, and sleep as compared to healthy controls. Method: Thirty-eight patients (18 females and 20 males; mean age: 56.06 years) diagnosed with RLS and an age- and gender-matched control group (n = 42) were recruited. Participants completed a series of questionnaires related to locus of control, personality traits, quality of life, and sleep. Results: Compared to healthy controls, RLS patients had a lower internal locus of control, unfavourable sleep-related personality traits such as low self-confidence and higher mental arousal, poorer quality of life, and more depressive symptoms. Sleep was also affected. Multiple regression analyses showed that a low internal and a high external locus of control were predicted by RLS. Conclusions: The pattern of results suggests that RLS is associated with a low locus of control, negative personality traits, and poor quality of life as compared to healthy controls.
EML4-ALK-Positive Pulmonary Adenocarcinoma with an Unusual Metastatic Pattern: A Case Report
Authors: Diem Stefan , Früh Martin , Rodriguez Regulo , Liechti Peter , Rothermundt Christian
Published: June 2013

Background: Non-small cell adenocarcinoma is a frequent tumour entity with a high mortality. Insight into molecular mechanisms has led to the development of promising therapeutic options, which improve the prognosis of affected patients. There are only a few reports on molecular tumour subtypes and clinical presentation of the disease. We present the case of a patient with anaplastic lymphoma kinase (ALK)-positive adenocarcinoma of the lung with an unusual metastatic pattern. Conclusion: The metastatic pattern of non-small cell lung cancer with ALK translocation may be different from other lung cancers. An uncommon clinical presentation may sensitize treating physicians to perform corresponding molecular testing in order to offer the best treatment options.
Risk Scores of Common Genetic Variants for Lipid Levels Influence Atherosclerosis and Incident Coronary Heart Disease
Authors: Isaacs Aaron , Willems Sara M. , Bos Daniel , Dehghan Abbas , Hofman Albert , Ikram M. Arfan , Uitterlinden André G. , Oostra Ben A. , Franco Oscar H. , Witteman Jacqueline C. , van Duijn Cornelia M.
Published: June 2013

Objective—

Circulating levels of total cholesterol, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol, and triglycerides are recognized risk factors for cardiovascular disease. We tested the hypothesis that the cumulative effects of common genetic variants for lipids are collectively associated with subclinical atherosclerosis and incident coronary heart disease.

Approach and Results—

Participants were drawn from the Erasmus Rucphen Family Study (n=2269) and the Rotterdam Study (n=8130). Linear regression and Cox proportional hazards models were applied to assess the influence of 4 risk scores derived from common genetic variants for lipids (total cholesterol, LDL-C, high-density lipoprotein cholesterol, and triglycerides) on carotid plaque, intima-media thickness, incident myocardial infarction, and coronary heart disease. Adjusted for age and sex, all 4 risk scores were associated with carotid plaque. This relationship was the strongest for the LDL-C score, which increased plaque score by 0.102 per SD increase in genetic risk score (
P
=3.2×10
−8
). The LDL-C score was also nominally associated with intima-media thickness, which increased 0.006 mm per SD increase in score (
P
=0.05). Both the total cholesterol and LDL-C scores were associated with incident myocardial infarction and coronary heart disease with hazard ratios between 1.10 and 1.13 per SD increase in score. Inclusion of additional risk factors as covariates minimally affected these results.

Conclusions—

Common genetic variants with small effects on lipid levels are, in combination, significantly associated with subclinical and clinical cardiovascular outcomes. As knowledge of genetic variation increases, preclinical genetic screening tools might enhance the prediction and prevention of clinical events.
Cathelicidin LL-37 Induces Angiogenesis via PGE
2
–EP3 Signaling in Endothelial Cells, In Vivo Inhibition by Aspirin
Authors: Salvado M. Dolores , Di Gennaro Antonio , Lindbom Lennart , Agerberth Birgitta , Haeggström Jesper Z.
Published: June 2013

Objective—

LL-37, the unique cathelicidin expressed in humans, in addition to acting as an endogenous antibiotic, is an important cell-signaling molecule upregulated in ovarian, breast, and lung tumors. However, the role of LL-37 in tumor microenvironment and its specific actions on the endothelial compartment remain elusive. Prostanoids are key regulators of inflammation, and cyclooxygenases (COXs) display proangiogenic activity in vitro and in vivo, mediated principally through prostaglandin E
2
(PGE
2
). Here, we provide evidence for a novel proangiogenic role of LL-37, exerted via activation of endothelial cells and subsequent PGE
2
biosynthesis.

Approach and Results—

LL-37 triggers PGE
2
synthesis in endothelial cells in a dose-dependent manner with maximal induction after 4 hours. Endothelial PGE
2
biosynthesis was dependent on COX-1, rather than COX-2, as judged by pharmacological inhibition and gene silencing. In vitro matrigel assays supported these findings because LL-37–induced cord formation was abolished by COX-1, but not COX-2, small interfering RNA, and the angiogenic phenotype could be rescued by addition of exogenous PGE
2
. We find that LL-37 acts on endothelial cells as a potent calcium agonist, inducing phosphorylation and activation of cytosolic phospholipase A
2
(cPLA
2
), promoting a cPLA
2
→COX-1→PGE
2
biosynthetic pathway and subsequent signaling via PGE
2
receptor EP3. Moreover, cathelicidin-related antimicrobial peptide, which is the murine ortholog of LL-37, induced prostaglandin-dependent angiogenesis in vivo, which could be blocked by aspirin.

Conclusions—

Our results identify a novel proangiogenic role of LL-37, suggesting that the axis LL-37/COX-1/PGE
2
followed by EP3 signaling is amenable to therapeutic intervention in pathological angiogenesis, for instance by aspirin.
Infant Ventricular Fibrillation After ST-Segment Changes and QRS Widening
Authors: Miyake Christina Y. , Davis Andrew M. , Motonaga Kara S. , Dubin Anne M. , Berul Charles I. , Cecchin Frank
Published: June 2013

Background—

Ventricular arrhythmia–related sudden cardiac arrest in infants with structurally normal hearts is rare. There have been no previously published reports of infants <3 months of age with ventricular fibrillation in which a primary diagnosis could not be defined.

Methods and Results—

Retrospective chart review of 3 unrelated infants <2 months of age from 3 different tertiary care centers within the United States and Australia was conducted. All 3 infants survived sudden cardiac arrest secondary to multiple episodes of polymorphic ventricular tachycardia and ventricular fibrillation. Each infant demonstrated unique and transient ECG findings consisting of ST changes and QRS widening before arrhythmia onset, which have not been previously reported. Amiodarone, sedation, sodium channel–blocking agents, and ventricular pacing were effective in suppressing acute events. Despite thorough investigation, including genetic testing, the cause of ventricular arrhythmias in each of these infants remains unclear.

Conclusions—

This is the first report of idiopathic ventricular fibrillation in young infants preceded by stereotypical transient ECG changes. These findings may represent a new, potentially treatable cause of sudden infant death. Recognition of these prodromal changes may be important in future management and survival of these infants.