bluuebunny/crossref_metadata_2025 huggingface dataset:
CME Information:Sexuality Education in North American Medical Schools: Current Status and Future Directions (CME)
Authors: Shindel Alan W. , Parish Sharon J.
Published: January 2013

Introduction

Both the general public and individual patients expect healthcare providers to be knowledgeable and approachable regarding sexual health. Despite this expectation there are no universal standards or expectations regarding the sexuality education of medical students.

Aims

To review the current state of the art in sexuality education for North American medical students and to articulate future directions for improvement.

Methods

Evaluation of: (i) peer-reviewed literature on sexuality education (focusing on undergraduate medical students); and (ii) recommendations for sexuality education from national and international public health organizations.

Main Outcome Measures

Current status and future innovations for sexual health education in North American medical schools.

Results

Although the importance of sexuality to patients is recognized, there is wide variation in both the quantity and quality of education on this topic in North American medical schools. Many sexual health education programs in medical schools are focused on prevention of unwanted pregnancy and sexually transmitted infection. Educational material on sexual function and dysfunction, female sexuality, abortion, and sexual minority groups is generally scant or absent. A number of novel interventions, many student initiated, have been implemented at various medical schools to improve the student's training in sexual health matters.

Conclusions

There is a tremendous opportunity to mold the next generation of healthcare providers to view healthy sexuality as a relevant patient concern. A comprehensive and uniform curriculum on human sexuality at the medical school level may substantially enhance the capacity of tomorrow's physicians to provide optimal care for their patients irrespective of gender, sexual orientation, and individual sexual mores/beliefs.
Fiscal Policy, Monetary Regimes and Current Account Dynamics
Authors: Herz Bernhard , Hohberger Stefan
Published: January 2013

For the individual European Monetary Union (EMU) members fiscal policy has gained in importance owing to the loss of monetary policy as an autonomous policy instrument. Based on a small open economy dynamic stochastic general equilibrium (DSGE) model with fiscal feedback rules, we analyze the dynamic macroeconomic response in particular of the current account under alternative exchange rate regimes. Our results indicate that entry into monetary union makes the economy more vulnerable to a productivity shock and leads to higher variability of the current account. For a risk premium shock, an entry into EMU implies lower variability of most macroeconomic variables, but a higher persistence in the adjustment process of the current account. For both shocks, a countercyclical fiscal response to the current account is more stabilizing for most macroeconomic variables than a conventional countercyclical response to output. Stabilizing the current account comes at the price of higher variability of output in the short‐run, however.
Parametric Excitation and Evolutionary Dynamics
Authors: Ruelas Rocio E. , Rand David G. , Rand Richard H.
Published: January 2013

Parametric excitation refers to dynamics problems in which the forcing function enters into the governing differential equation as a variable coefficient. Evolutionary dynamics refers to a mathematical model of natural selection (the “replicator” equation) which involves a combination of game theory and differential equations. In this paper we apply perturbation theory to investigate parametric resonance in a replicator equation having periodic coefficients. In particular, we study evolution in the Rock-Paper-Scissors game, which has biological and social applications. Here periodic coefficients could represent seasonal variation. We show that 2:1 subharmonic resonance can destabilize the usual “Rock-Paper-Scissors” equilibrium for parameters located in a resonant tongue in parameter space. However, we also show that the tongue may be absent or very small if the forcing parameters are chosen appropriately.
Residue-free plasma etching of polyimide coatings for small pitch vias with improved step coverage
Authors: Mimoun Benjamin , Pham Hoa T. M. , Henneken Vincent , Dekker Ronald
Published: January 2013

The authors have found that patterning polyimide coatings containing organosilane adhesion promoter using pure oxygen plasma resulted in a thin silicon-rich residue layer. They show in this paper that adding small amounts of fluorine-containing gas to the etching gas mixture is necessary in order to achieve residue-free polyimide plasma etching. They report residue-free plasma etching of polyimide coatings with both isotropic and anisotropic profiles, using either metal or oxide hard masks. These etching methods are however not sufficient for the fabrication of high density metal filled vias in 10 μm thick polyimide coatings. In order to improve the metal step coverage over the vias while keeping the pitch as small as possible, the authors have developed a two-step etching recipe combining both isotropic and anisotropic profiles, resulting in wine-glass shaped vias.
252Cf fission-neutron spectrum using a simplified time-of-flight setup: An advanced teaching laboratory experiment
Authors: Becchetti F. D. , Febbraro M. , Torres-Isea R. , Ojaruega M. , Baum L.
Published: January 2013

The removal of PuBe and AmBe neutron sources from many university teaching laboratories (due to heightened security issues) has often left a void in teaching various aspects of neutron physics. We have recently replaced such sources with sealed 252Cf oil-well logging sources (nominal 10–100 μCi), and developed several experiments using them as neutron sources. This includes a fission-neutron time-of-flight experiment using plastic scintillators, which utilizes the prompt γ rays emitted in 252Cf spontaneous fission as a fast timing start signal. The experiment can be performed with conventional nuclear instrumentation and a 1-D multi-channel pulse-height analyzer, available in most advanced teaching laboratories. Alternatively, a more sophisticated experiment using liquid scintillators and n/γ pulse-shape discrimination can be performed. Several other experiments using these neutron sources are also feasible. The experiments can introduce students to the problem of detecting the dark matter thought to dominate the universe and to the techniques used to detect contraband fissionable nuclear materials.
Culture of Impact: Faculty as Mentors for Student Entrepreneurs
Authors: Prestwich Glenn D.
Published: January 2013

Students are the entrepreneurs on campus and need experienced faculty mentors.
Pancreatic Digestive Enzyme Blockade in the Intestine Increases Survival After Experimental Shock
Authors: DeLano Frank A. , Hoyt David B. , Schmid-Schönbein Geert W.
Published: January 2013

Blockade of pancreatic digestive enzymes in the intestine ameliorates shock and multiorgan failure and improves survival in rodents.
DNA Methylation Alterations Exhibit Intraindividual Stability and Interindividual Heterogeneity in Prostate Cancer Metastases
Authors: Aryee Martin J. , Liu Wennuan , Engelmann Julia C. , Nuhn Philipp , Gurel Meltem , Haffner Michael C. , Esopi David , Irizarry Rafael A. , Getzenberg Robert H. , Nelson William G. , Luo Jun , Xu Jianfeng , Isaacs William B. , Bova G. Steven , Yegnasubramanian Srinivasan
Published: January 2013

Prostate tumors develop a unique epigenetic DNA methylation signature that is clonally maintained in disseminated metastases.
The Trojan Horse for Hematologic Malignancies
Authors: Tanhehco Yvette
Published: January 2013

siRNAs targeting STAT3 decrease survival of tumor cells and activate the host immune system.
Characterization of BcaA, a Putative Classical Autotransporter Protein in Burkholderia pseudomallei
Authors: Campos Cristine G. , Borst Luke , Cotter Peggy A.
Published: January 2013

Burkholderia pseudomallei
is a tier 1 select agent, and the causative agent of melioidosis, a disease with effects ranging from chronic abscesses to fulminant pneumonia and septic shock, which can be rapidly fatal. Autotransporters (ATs) are outer membrane proteins belonging to the type V secretion system family, and many have been shown to play crucial roles in pathogenesis. The open reading frame Bp1026b_II1054 (
bcaA
) in
B. pseudomallei
strain 1026b is predicted to encode a classical autotransporter protein with an approximately 80-kDa passenger domain that contains a subtilisin-related domain. Immediately 3′ to
bcaA
is Bp11026_II1055 (
bcaB
), which encodes a putative prolyl 4-hydroxylase. To investigate the role of these genes in pathogenesis, large in-frame deletion mutations of
bcaA
and
bcaB
were constructed in strain Bp340, an efflux pump mutant derivative of the melioidosis clinical isolate 1026b. Comparison of Bp340Δ
bcaA
and Bp340Δ
bcaB
mutants to wild-type
B. pseudomallei
in vitro
demonstrated similar levels of adherence to A549 lung epithelial cells, but the mutant strains were defective in their ability to invade these cells and to form plaques. In a BALB/c mouse model of intranasal infection, similar bacterial burdens were observed after 48 h in the lungs and liver of mice infected with Bp340Δ
bcaA
, Bp340Δ
bcaB
, and wild-type bacteria. However, significantly fewer bacteria were recovered from the spleen of Bp340Δ
bcaA
-infected mice, supporting the idea of a role for this AT in dissemination or in survival in the passage from the site of infection to the spleen.
Tricuspid valve thrombus causing acute pulmonary embolism
Authors: Gunduz Yasemin , Ucar Aysenur , Vatan Mehmet Bulent , Keser Nurgul
Published: January 2013

The development of thrombus on the tricuspid valve is very rare in adulthood and it needs special attention in clinical practice as it can be confused with vegetation or a tumour. Embolisation due to thrombus may have an acute and unexpected course with a detrimental prognosis and a high death rate during the first 24 h after diagnosis. In this report, we presented a case of mobile tricuspid valve thrombus detected by transthoracic echocardiography that led to recurrent pulmonary embolism.
Rituximab seems a promising therapeutic option in granulomatosis with polyangiitis with intestinal perforation: a case report and literature review
Authors: Dag Muhammet Sait , Pehlivan Yavuz , Tutar Ediz , Kisacik Bunyamin
Published: January 2013

Granulomatosis with polyangiitis (Wegener's) (GPA) is a chronic disease of unknown aetiology that leads to necrotising vasculitis in small and medium-sized vessels characterised by respiratory system and kidney involvement. Intestinal involvement is rare and perforation is even rarer in GPA. In this study, we are presenting a literature review of related cases, and a 29-year-old man referred from the emergency department with a multiple distal ileal perforation that was diagnosed with GPA, and successfully treated with rituximab.
Two cross-linked porcine dermal implants in a single patient undergoing hernia repair
Authors: Linz Luke A , Burke Leandra H , Miller Lisa A
Published: January 2013

A 50-year-old woman with a history of multiple recurrent incisional hernias and multiple comorbidities received two different porcine dermal implants during the same procedure due to the availability of products in stock. At 3.5 months following this procedure, the patient developed a secondary hernia inferior and lateral to the site of previous surgery. Both the implants were biopsied and sent for pathological evaluation. One implant was compliant and well integrated while the other was non-compliant and exhibited extensive foreign body reaction. In this case report, we examine the differences between the two porcine implants that may have caused them to react so differently in the same subject under the same conditions.
Illustrative cases of false positive biopsies after stereotactic body radiation therapy for lung cancer based on abnormal FDG-PET-CT imaging
Authors: Singhvi Mamta , Lee Percy
Published: January 2013

Stereotactic body radiation therapy (SBRT) for early stage lung cancer has made significant strides as an alternative to surgery.1 We present two cases of non-small cell lung cancer treated with SBRT and then followed serially with imaging in which suspicion of recurrence led to biopsies.
Simultaneous hypertensive intracerebral haemorrhages: what are the odds?
Authors: Amin Osama S M
Published: January 2013

The simultaneous development of two (or more) spontaneous, hypertensive, non-traumatic intraparenchymal cerebral haemorrhages is rare and constitutes less than 5.6% of all hypertensive cerebral haemorrhages. In addition to having a high early mortality, these haemorrhages carry a considerable morbidity figure in patients who survive the event. We report a 68-year-old hypertensive and diabetic woman who presented with a sudden onset of headache, vomiting, and dense right-sided weakness. In less than an hour, she became obtunded. An urgent non-contrast CT brain scan revealed two left-sided supratentorial hemispheric haemorrhages; putamenal and thalamic.
Bilateral taurodontism in primary dentition with hypodontia
Authors: Surendar Marappan Natarajan , Pandey Ramesh Kumar , Khanna Richa
Published: January 2013

Taurodontism is a rare dental anomaly in which there is an enlarged pulp chamber at the expense of roots with apical displacement of the pulpal floor, giving it a rectangular shape. It is caused by the failure of Hertwig's epithelial root sheath to invaginate at the proper horizontal level. Taurodontism has been reported as an intraoral feature of several syndromes like Down syndrome, Klinefelter syndrome, Smith-Magenis syndrome, Hurler syndrome, etc. Association of taurodontism with hypodontia in permanent dentition has also been reported. Taurodontism in primary dentition and its association with hypodontia is very rarely reported in the literature. The present case illustrates bilateral taurodontism of primary mandibular molars with hypodontia in maxilla.
Framework geophysical modelling of granitoid versus supracrustal basement to the northeast Thelon Basin around the Kiggavik uranium camp, Nunavut
Authors: Tschirhart V. , Morris W.A. , Jefferson C.W.
Published: January 2013

The northeast Thelon Basin in the Kivalliq region of Nunavut is prospective for uranium deposits. Recently discovered basement-hosted, unconformity-associated prospects west of Kiggavik are restricted to deformed and metamorphosed Neoarchean psammitic enclaves of the Woodburn Lake group within 1.83 Ga Hudson granite and Martell syenite that together comprise the Shultz Lake intrusive complex (SLIC). The depth and geometry of the intrusive complex are relatively unknown as the geological constraints are poor; the drilling is sparse and of shallow depth extent as it was not targeting the basement but shallower multiply faulted and highly altered demagnetized zones. This study aims to constrain the geometry and context of the Shultz Lake intrusive complex with respect to the ore-hosting Neoarchean metasedimentary rocks and intersecting reactivated fault arrays through geophysical modelling of detailed aeromagnetic and gravity data integrated with new geological knowledge. By integrating detailed gravity, aeromagnetic, and structural geology observations measured along a series of transects with a petrophysical rock properties database, it is possible to derive constraints on the depth and thickness (200–300 m) of the SLIC. Quantitative comparison and integration of multiple hypothetical geometries favours a model wherein the SLIC, together with metasedimentary and older basement gneiss, has been structurally emplaced over the Neoarchean metasediments.
H2S signaling in redox regulation of cellular functions
Authors: Ju Youngjun , Zhang Weihua , Pei Yanxi , Yang Guangdong
Published: January 2013

Hydrogen sulfide (H2S) is traditionally recognized as a toxic gas with a rotten-egg smell. In just the last few decades, H2S has been found to be one of a family of gasotransmitters, together with nitric oxide and carbon monoxide, and various physiologic effects of H2S have been reported. Among the most acknowledged molecular mechanisms for the cellular effects of H2S is the regulation of intracellular redox homeostasis and post-translational modification of proteins through S-sulfhydration. On the one side, H2S can promote an antioxidant effect and is cytoprotective; on the other side, H2S stimulates oxidative stress and is cytotoxic. This review summarizes our current knowledge of the antioxidant versus pro-oxidant effects of H2S in mammalian cells and describes the Janus-faced properties of this novel gasotransmitter. The redox regulation for the cellular effects of H2S through S-sulfhydration and the role of H2S in glutathione generation is also recapitulated. A better understanding of H2S-regualted redox homeostasis will pave the way for future design of novel pharmacological and therapeutic interventions for various diseases.
ELECTROWEAK SYMMETRY BREAKING AND THE HIGGS BOSON: CONFRONTING THEORIES AT COLLIDERS
Authors: AZATOV ALEKSANDR , GALLOWAY JAMISON
Published: January 2013

In this review, we discuss methods of parsing direct information from collider experiments regarding the Higgs boson and describe simple ways in which experimental likelihoods can be consistently reconstructed and interfaced with model predictions in pertinent parameter spaces. We review prevalent scenarios for extending the electroweak symmetry breaking sector and emphasize their predictions for nonstandard Higgs phenomenology that could be observed in large hadron collider (LHC) data if naturalness is realized in particular ways. Specifically we identify how measurements of Higgs couplings can be used to imply the existence of new physics at particular scales within various contexts. The most dominant production and decay modes of the Higgs-like state observed in the early data sets have proven to be consistent with predictions of the Higgs boson of the Standard Model, though interesting directions in subdominant channels still exist and will require our careful attention in further experimental tests. Slightly anomalous rates in certain channels at the early LHC have spurred effort in model building and spectra analyses of particular theories, and we discuss these developments in some detail. Finally, we highlight some parameter spaces of interest in order to give examples of how the data surrounding the new state can most effectively be used to constrain specific models of weak scale physics.
Nanotechnology-based photodynamic therapy
Authors: Yoon Hee-Jae , Jang Woo-Dong
Published: January 2013

According to recent advances in nanotechnology, various nano-sized formulations have been designed for the application in biomedical fields, including diagnosis, drug delivery, and therapeutics. The nanotechnology-based formulations have a great merit in the design of multifunctional platform for the biomedical applications. Therefore, recent trends in nanotechnology are moving onto the combination of nanotechnology and conventional therapeutic. Typically, photodynamic therapy (PDT) is one of promising techniques for the combination with nanotechnology owing to its less invasiveness. In this paper, we are going to briefly review recent advances in nanotechnology-based PDT, including selective delivery and excitation of photosensitizers, combination therapy, and multifunctional PDT.
Central glucagon-like peptide 1 receptor-induced anorexia requires glucose metabolism-mediated suppression of AMPK and is impaired by central fructose
Authors: Burmeister Melissa A. , Ayala Jennifer , Drucker Daniel J. , Ayala Julio E.
Published: January 2013

Glucagon-like peptide-1 (GLP-1) suppresses food intake via activation of a central (i.e., brain) GLP-1 receptor (GLP-1R). Central AMP-activated protein kinase (AMPK) is a nutrient-sensitive regulator of food intake that is inhibited by anorectic signals. The anorectic effect elicited by hindbrain GLP-1R activation is attenuated by the AMPK stimulator AICAR. This suggests that central GLP-1R activation suppresses food intake via inhibition of central AMPK. The present studies examined the mechanism(s) by which central GLP-1R activation inhibits AMPK. Supporting previous findings, AICAR attenuated the anorectic effect elicited by intracerebroventricular (icv) administration of the GLP-1R agonist exendin-4 (Ex-4). We demonstrate that Ex-4 stimulates glycolysis and suppresses AMPK phosphorylation in a glucose-dependent manner in hypothalamic GT1-7 cells. This suggests that inhibition of AMPK and food intake by Ex-4 requires central glucose metabolism. Supporting this, the glycolytic inhibitor 2-deoxyglucose (2-DG) attenuated the anorectic effect of Ex-4. However, icv glucose did not enhance the suppression of food intake by Ex-4. AICAR had no effect on Ex-4-mediated reduction in locomotor activity. We also tested whether other carbohydrates affect the anorectic response to Ex-4. Intracerebroventricular pretreatment with the sucrose metabolite fructose, an AMPK activator, attenuated the anorectic effect of Ex-4. This potentially explains the increased food intake observed in sucrose-fed mice. In summary, we propose a model whereby activation of the central GLP-1R reduces food intake via glucose metabolism-dependent inhibition of central AMPK. We also suggest that fructose stimulates food intake by impairing central GLP-1R action. This has significant implications given the correlation between sugar consumption and obesity.
Human prostasomes express glycolytic enzymes with capacity for ATP production
Authors: Ronquist K. Göran , Ek Bo , Stavreus-Evers Anneli , Larsson Anders , Ronquist Gunnar
Published: January 2013

Prostasomes are prostate-derived, exosome-like microvesicles that transmit signaling complexes between the acinar epithelial cells of the prostate and sperm cells. The vast majority of prostasomes have a diameter of 30–200 nm, and they are generally surrounded by a classical membrane bilayer. Using a selected proteomic approach, it became increasingly clear that prostasomes harbor distinct subsets of proteins that may be linked to adenosine triphosphate (ATP) metabolic turnover that in turn might be of importance in the role of prostasomes as auxiliary instruments in the fertilization process. Among the 21 proteins identified, most of the enzymes of anaerobic glycolysis were represented, and three of the glycolytic enzymes present are among the top 10 proteins found in most exosomes, once again linking prostasomes to the exosome family. Other prostasomal enzymes involved in ATP turnover were adenylate kinase, ATPase, 5′-nucleotidase, and hexose transporters. The identified enzymes in their prostasomal context were operational for ATP formation when supplied with substrates. The net ATP production was low due to a high prostasomal ATPase activity that could be partially inhibited by vanadate that was utilized to profile the ATP-forming ability of prostasomes. Glucose and fructose were equivalent as glycolytic substrates for prostasomal ATP formation, and the enzymes involved were apparently surface located on prostasomes, since an alternative substrate not being membrane permeable (glyceraldehyde 3-phosphate) was operative, too. There is no clear-cut function linked to this subset of prostasomal proteins, but some possible roles are discussed.
Conformal Gravity and the Alcubierre Warp Drive Metric
Authors: Varieschi Gabriele U. , Burstein Zily
Published: January 2013

We present an analysis of the classic Alcubierre metric based on conformal gravity, rather than
standard general relativity. The main characteristics of the resulting warp drive remain the same as in the original study by Alcubierre, that is, effective superluminal motion is a viable outcome of the metric. We show that for particular choices of the shaping function, the Alcubierre metric in the context of conformal gravity does not violate the weak energy condition, as was the case of the original solution. In particular, the resulting warp drive does not require the use of exotic matter. Therefore, if conformal gravity is a correct extension of general relativity, superluminal motion via an Alcubierre metric might be a realistic solution, thus allowing faster-than-light interstellar travel.
Preclinical and Clinical Studies of Gamma Secretase Inhibitors with Docetaxel on Human Breast Tumors
Authors: Schott Anne F. , Landis Melissa D. , Dontu Gabriela , Griffith Kent A. , Layman Rachel M. , Krop Ian , Paskett Lacey A. , Wong Helen , Dobrolecki Lacey E. , Lewis Michael T. , Froehlich Amber M. , Paranilam Jaya , Hayes Daniel F. , Wicha Max S. , Chang Jenny C.
Published: January 2013

Purpose: Accumulating evidence supports the existence of breast cancer stem cells (BCSC), which are characterized by their capacity to self-renew and divide indefinitely and resistance to conventional therapies. The Notch pathway is important for stem cell renewal and is a potential target for BCSC-directed therapy.

Experimental Design: Using human breast tumorgraft studies, we evaluated the impact of gamma secretase inhibitors (GSI) on the BCSC population and the efficacy of combining GSI with docetaxel treatment. The mouse experimental therapy paralleled a concurrent clinical trial in patients with advanced breast cancer, designed to determine the maximum-tolerated dose of the GSI, MK-0752, administered sequentially with docetaxel, and to evaluate BCSC markers in serial tumor biopsies.

Results: Treatment with GSI reduced BCSCs in MC1 and BCM-2147 tumorgrafts by inhibition of the Notch pathway. GSI enhanced the efficacy of docetaxel in preclinical studies. In the clinical trial, 30 patients with advanced breast cancer were treated with escalating doses of MK-0752 plus docetaxel. Clinically, meaningful doses of both drugs were possible with manageable toxicity and preliminary evidence of efficacy. A decrease in CD44+/CD24−, ALDH+, and mammosphere-forming efficiency were observed in tumors of patients undergoing serial biopsies.

Conclusions: These preclinical data show that pharmacologic inhibition of the Notch pathway can reduce BCSCs in breast tumorgraft models. The clinical trial shows feasibility of combination GSI and chemotherapy, and together these results encourage further study of Notch pathway inhibitors in combination with chemotherapy in breast cancer. Clin Cancer Res; 19(6); 1512–24. ©2012 AACR.
ZEB1 Promotes Invasiveness of Colorectal Carcinoma Cells through the Opposing Regulation of uPA and PAI-1
Authors: Sánchez-Tilló Ester , de Barrios Oriol , Siles Laura , Amendola Pier G. , Darling Douglas S. , Cuatrecasas Miriam , Castells Antoni , Postigo Antonio
Published: January 2013

Purpose: Carcinoma cells enhance their invasive capacity through dedifferentiation and dissolution of intercellular adhesions. A key activator of this process is the ZEB1 transcription factor, which is induced in invading cancer cells by canonical Wnt signaling (β-catenin/TCF4). Tumor invasiveness also entails proteolytic remodeling of the peritumoral stroma. This study aimed to investigate the potential regulation by ZEB1 of the plasminogen proteolytic system constituted by the urokinase plasminogen activator (uPA), and its inhibitor, plasminogen activator inhibitor-1 (PAI-1).

Experimental Design: Through multiple experimental approaches, colorectal carcinoma (CRC) cell lines and samples from human primary CRC and ZEB1 (−/−) mice were used to examine ZEB1-mediated regulation of uPA and PAI-1 at the protein, mRNA, and transcriptional level.

Results: ZEB1 regulates uPA and PAI-1 in opposite directions: induces uPA and inhibits PAI-1. In vivo expression of uPA depends on ZEB1 as it is severely reduced in the developing intestine of ZEB1 null (−/−) mice. Optimal induction of uPA by Wnt signaling requires ZEB1 expression. ZEB1 binds to the uPA promoter and activates its transcription through a mechanism implicating the histone acetyltransferase p300. In contrast, inhibition of PAI-1 by ZEB1 does not involve transcriptional repression but rather downregulation of mRNA stability. ZEB1-mediated tumor cell migration and invasion depend on its induction of uPA. ZEB1 coexpresses with uPA in cancer cells at the invasive front of CRCs.

Conclusions: ZEB1 promotes tumor invasiveness not only via induction in cancer cells of a motile dedifferentiated phenotype but also by differential regulation of genes involved in stroma remodeling. Clin Cancer Res; 19(5); 1071–82. ©2013 AACR.
Rab25 Regulates Invasion and Metastasis in Head and Neck Cancer
Authors: Amornphimoltham Panomwat , Rechache Kamil , Thompson Jamie , Masedunskas Andrius , Leelahavanichkul Kantima , Patel Vyomesh , Molinolo Alfredo , Gutkind J. Silvio , Weigert Roberto
Published: January 2013

Purpose: Head and neck squamous cell carcinoma (HNSCC) is one of the 10 most common cancers with a 50% five-year survival rate, which has remained unchanged for the past three decades. One of the major reasons for the aggressiveness of this cancer is that HNSCCs readily metastasize to cervical lymph nodes that are abundant in the head and neck region. Hence, discovering new molecules controlling the metastatic process as well as understanding their regulation at the molecular level are essential for effective therapeutic strategies.

Experimental Design: Rab25 expression level was analyzed in HNSCC tissue microarray. We used a combination of intravital microscopy in live animals and immunofluorescence in an in vitro invasion assay to study the role of Rab25 in tumor cell migration and invasion.

Results: In this study, we identified the small GTPase Rab25 as a key regulator of HNSCC metastasis. We observed that Rab25 is downregulated in HNSCC patients. Next, we determined that reexpression of Rab25 in a metastatic cell line is sufficient to block invasion in a three-dimensional collagen matrix and metastasis to cervical lymph nodes in a mouse model for oral cancer. Specifically, Rab25 affects the organization of F-actin at the cell surface, rather than cell proliferation, apoptosis, or tumor angiogenesis.

Conclusion: These findings suggest that Rab25 plays an important role in tumor migration and metastasis, and that understanding its function may lead to the development of new strategies to prevent metastasis in oral cancer patients. Clin Cancer Res; 19(6); 1375–88. ©2013 AACR.
Prognostic and Predictive Value of Tumor Vascular Endothelial Growth Factor Gene Amplification in Metastatic Breast Cancer Treated with Paclitaxel with and without Bevacizumab; Results from ECOG 2100 Trial
Authors: Schneider Bryan P. , Gray Robert J. , Radovich Milan , Shen Fei , Vance Gail , Li Lang , Jiang Guanglong , Miller Kathy D. , Gralow Julie R. , Dickler Maura N. , Cobleigh Melody A. , Perez Edith A. , Shenkier Tamara N. , Vang Nielsen Kirsten , Müller Sven , Thor Ann , Sledge George W. , Sparano Joseph A. , Davidson Nancy E. , Badve Sunil S.
Published: January 2013

Purpose: Clinically validated biomarkers for anti-angiogenesis agents are not available. We have previously reported associations between candidate VEGFA single-nucleotide polymorphisms (SNP) and overall survival (OS) in E2100. The associations between tumor VEGFA amplification and outcome are evaluated here.

Experimental Design: E2100 was a phase III trial comparing paclitaxel with or without bevacizumab for patients with metastatic breast cancer. FISH to assess gene amplification status for VEGFA was conducted on paraffin-embedded tumors from 363 patients in E2100. Evaluation for association between amplification status and outcomes was conducted.

Results: Estrogen receptor (ER)+ or progesterone receptor (PR)+ tumors were less likely to have VEGFA amplification than ER/PR− tumors (P = 0.020). VEGFA amplification was associated with worse OS (20.2 vs. 25.3 months; P = 0.013) in univariate analysis with a trend for worse OS in multivariate analysis (P = 0.08). There was a significant interaction between VEGFA amplification, hormone receptor status, and study arm. Patients with VEGFA amplification and triple-negative breast cancers (TNBC) or HER2 amplification had inferior OS (P = 0.047); amplification did not affect OS for those who were ER+ or PR+ and HER2−. Those who received bevacizumab with VEGFA amplification had inferior progression-free survival (PFS; P = 0.010) and OS (P = 0.042); no association was seen in the control arm. Test for interaction between study arm and VEGFA amplification with OS was not significant.

Conclusion: VEGFA amplification in univariate analysis was associated with poor outcomes; this was particularly prominent in HER2+ or TNBCs. Additional studies are necessary to confirm the trend for poor OS seen on multivariate analysis for patients treated with bevacizumab. Clin Cancer Res; 19(5); 1281–9. ©2012 AACR.
Can the “Right” EGFR-Specific mAb Dramatically Improve EGFR-Targeted Therapy?
Authors: Sabbatino Francesco , Ferrone Soldano
Published: January 2013

EGF receptor (EGFR)–specific monoclonal antibodies (mAb) display limited therapeutic efficacy in EGFR-positive solid tumors. To overcome this limitation, the significant improvement of the antibody-dependent cell-mediated cytotoxicity–mediated antitumor activity of a novel EGFR-specific mAb is described. Its potential impact on the efficacy of immunotherapy for EGFR-positive solid tumors is discussed. Clin Cancer Res; 19(5); 958–60. ©2013 AACR.
Characterization of Candidate Anti-Allergic Probiotic Strains in a Model of Th2-Skewed Human Peripheral Blood Mononuclear Cells
Authors: Holvoet Sébastien , Zuercher Adrian W. , Julien-Javaux Françoise , Perrot Marie , Mercenier Annick
Published: January 2013

Background: Pre-clinical and clinical studies have evaluated the efficacy of probiotics in allergy. However, predictive in vitro systems for rational strain selection are still missing. Methods: We developed a novel in vitro screening system for the characterization of probiotics with anti-allergic potential. In this model, human peripheral blood mononuclear cells (PBMC) from healthy donors (n = 68) were skewed towards a Th2 cytokine phenotype by culture with IL-4 and anti-CD40, to resemble cells from allergic donors. Th2-skewed cells were then co-cultured with probiotics; a total of 35 strains were tested. Levels of IFN-γ, IL-10, IL-5 and 7 additional cytokines in culture supernatants were determined by ELISA or multiplex assay. Gene expression was assessed by real-time PCR. For validation, splenocytes from ovalbumin-primed mice and PBMC from grass-allergic donors were restimulated with respective antigen and co-cultured with probiotics, and cytokine profiles were correlated. Results: Culture with IL-4 and anti-CD40 antibody induced secretion of IL-5 from PBMC, indicative of induction of a Th2 phenotype. Cytokine profiles induced by probiotics were strain specific even though species- and genus-specific clustering was observed for many strains by principal component analysis. This was paralleled by mRNA levels of the corresponding genes such as increased Tbet and reduced GATA-3 gene expression. Cytokine profiles induced by probiotics in PBMC stimulated with IL-4 and anti-CD40 correlated with those obtained from allergen-stimulated murine splenocytes or human PBMC from grass-allergic donors. Conclusions: Cytokine profiling of probiotic strains with IL-4-/anti-CD40-stimulated PBMC allowed to determine the effect of probiotics on Th2-skewed cells and thus to classify probiotic strains with anti-allergic potential.
Cariporide, a Specific Na+/H+ Exchanger 1 Blocker, Inhibits Neointimal Proliferation Induced by Advanced Glycation End Products in a Balloon Injury Rat Model
Authors: Wu Shujin , Yang Qingshan , Liu Qianqian , Song Tao , Zhou Shouhong , Liu Yuhui , Liu Liying
Published: January 2013

Aims: The association between diabetes and neointimal expansion after vascular injury has been attributed to the accumulation of advanced glycation end products (AGEs). Here we investigated the inhibitory effect of cariporide, a specific Na+/H+ exchanger 1 blocker, on neointimal proliferation induced by AGEs in a balloon injury model. Methods: Expression of cyclooxygenase-2 (COX-2) and matrix metalloproteinase (MMP) was monitored by reverse transcription-polymerase chain reaction (RT-PCR) and real-time PCR. The level of reactive oxygen species (ROS) was determined by specific fluorescent probe. The phosphorylation of the nuclear factor-ĸB (NF-ĸB) system was studied by Western blot. Results: Cariporide significantly suppressed AGE-induced neointimal hyperplasia, vascular smooth muscle cell (VSMC) proliferation, COX-2, MMP-2 and MMP-9 expression. In addition, cariporide decreased AGE-induced ROS, malondiadehyde level and increased the superoxide dismutase and glutathione peroxidase activity. We also found that cariporide blocked AGE-induced NF-ĸB activation and inhibitor-ĸB degradation. Conclusions: The results indicated that cariporide inhibited AGE-induced neointimal formation by suppressing the VSMC proliferation and the up-regulation of COX-2, MMP-2, MMP-9 via inhibiting ROS and NF-ĸB activation.
Gene Polymorphisms as Clinical Tools in Chronic Glomerulopathies: A Prospective Study
Authors: Chapdelaine Isabelle , Goupil Rémi , Azcoitia Valeria , Rioux Jean-Philippe , Raymond-Carrier Stéphanie , Madore François , Troyanov Stéphan
Published: January 2013

Background/Aims: Studies have proposed various polymorphisms of genes implicated in the physiopathology of chronic kidney disease as risk factors of progression and potential clinical tools. We sought to validate and simultaneously compare their predictive value in a prospective cohort of chronic glomerulopathies receiving recommended antihypertensive and antiproteinuric therapies. Methods: Using PubMed, we identified 9 polymorphisms previously associated with progression. These were mostly of the renin-angiotensin-aldosterone and inflammation pathways: MCP-1 A2518G, TGF-β1 T869C and C-509T, ACE I/D, AGT M235T, AT1R A1166C, TSC-22 A-396G, eNOS 4b/a and CYP11β2 C-344T. We hypothesized that their determination would identify individuals at higher risk of progression. Results: We recruited 93 predominantly male and Caucasian patients with a mean age of 63 and baseline eGFR of 33 ml/min/1.73 m2 followed prospectively over a median of 36 months. 61% of patients had diabetic nephropathy, almost all received RAA blockade (90%) and none immunosuppressive therapy. The average blood pressure during follow-up was 140/72 mm Hg, the urinary protein to creatinine ratio 0.15 g/mmol and the rate of renal function decline –3.2 ± 4.1 ml/min/1.73 m2/year. Proteinuria and blood pressure strongly predicted progression. However, under recommended therapy, none of the proposed polymorphisms predicted renal function decline. In addition, none showed simple or partial correlations with the severity of proteinuria or blood pressure. Finally, summation variable of risk polymorphisms did not predict progression. Conclusion: This study does not validate the use of these 9 polymorphisms as individual clinical tools in patients with chronic glomerulopathies on recommended antihypertensive and antiproteinuric therapies.
Microinvasion of High-Grade Pancreatic Intraepithelial Neoplasia
Authors: Kawada Natsuko , Uehara Hiroyuki , Takada Ryoji , Yamai Takuo , Fukutake Nobuyasu , Katayama Kazuhiro , Takenaka Akemi , Nagata Shigenori , Tomita Yasuhiko
Published: January 2013

High-grade pancreatic intraepithelial neoplasia (PanIN-3) is recognized as a precursor lesion of invasive ductal carcinoma (IDC). However, histological evidence that PanIN-3 invades beyond the basement membrane of pancreatic ductal epithelium, that is, the moment PanIN-3 becomes IDC, has not been captured yet. This may be because PanINs which are microscopic papillary or flat lesion rarely develop clinical symptoms and are not detectable on imaging examination. On the other hand, most IDCs were found in the advanced stage with massive invasion. In this report, PanIN-3 obstructed several branch pancreatic ducts and subsequently caused pancreatitis which developed clinical symptom and was detectable as a pancreatic mass in imaging studies. A 65-year-old woman was referred to our institution for further examination of her repeated pancreatitis. Abdominal ultrasound revealed a low echoic mass of 13 mm in diameter in the pancreatic body without upstream dilatation of the main pancreatic duct (MPD). Endoscopic retrograde pancreatography showed a strictured segment of 2 mm in length in the MPD at the pancreatic body. Cytological examination of pancreatic juice revealed adenocarcinoma and distal pancreatectomy was performed. A resected specimen revealed a whitish mass of 15 mm in diameter in the pancreatic body, which was identified as pancreatitis by histological examination. Papillary growth of PanIN-3 was seen mainly in the branch ducts. Each PanIN-3 was located separately in the branch ducts with normal epithelia in the MPD between them. In three adjacent branch ducts, PanIN-3 was observed to be invading microscopically beyond the basement membrane.
Transcatheter Closure of Post-myocardial Infarction Ventricular Septal Rupture
Authors: Assenza Gabriele Egidy , McElhinney Doff B. , Valente Anne Marie , Pearson Disty D. , Volpe Massimo , Martucci Giuseppe , Landzberg Michael J. , Lock James E.
Published: January 2013

Background—

Ventricular septal rupture (VSR) after acute myocardial infarction (AMI) is a potentially lethal mechanical complication of acute coronary syndromes. Given high surgical mortality, transcatheter closure has emerged as a potential strategy in selected cases. We report our single-center experience with double-umbrella device percutaneous closure of post-AMI VSR.

Methods and Results—

In this single-center, retrospective, cohort study, patients who underwent transcatheter closure of post-AMI VSR between 1988 and 2008 at Boston Children’s Hospital were included. Data were analysed according to whether the patients underwent direct percutaneous VSR closure or closure of a residual VSR after a previous surgical approach. Primary outcome was mortality rate at 30 days. Clinical predictors of primary outcome were investigated using univariate logistic regression. Thirty patients were included in the study (mean age, 67±8 years). A total of 40 closure devices were implanted. Major periprocedural complications occurred in 4 (13%) patients. Cardiogenic shock, increasing pulmonary/systemic flow ratio, and the use of the new generation (6-arm) STARFlex device all were associated with higher risk of mortality. The Model for End-Stage Liver Disease Excluding international normalized ratio (MELD-XI) score at the time of VSR closure seemed to be most strongly associated with death (odds ratio, 1.6; confidence interval, 1.1–2.2;
P
<0.001).

Conclusions—

Transcatheter closure of post-AMI VSR using CardioSEAL or STARFlex devices is feasible and effective. The MELD-XI score, a marker of multiorgan dysfunction, is a promising risk stratifier in this population of patients. Early closure of post-AMI VSR is advisable before establishment of multiorgan failure.
Duration of Cardiopulmonary Resuscitation and Illness Category Impact Survival and Neurologic Outcomes for In-hospital Pediatric Cardiac Arrests
Authors: Matos Renée I. , Watson R. Scott , Nadkarni Vinay M. , Huang Hsin-Hui , Berg Robert A. , Meaney Peter A. , Carroll Christopher L. , Berens Richard J. , Praestgaard Amy , Weissfeld Lisa , Spinella Philip C.
Published: January 2013

Background—

Pediatric cardiopulmonary resuscitation (CPR) for >20 minutes has been considered futile after pediatric in-hospital cardiac arrests. This concept has recently been questioned, although the effect of CPR duration on outcomes has not recently been described. Our objective was to determine the relationship between CPR duration and outcomes after pediatric in-hospital cardiac arrests.

Methods and Results—

We examined the effect of CPR duration for pediatric in-hospital cardiac arrests from the Get With The Guidelines–Resuscitation prospective, multicenter registry of in-hospital cardiac arrests. We included 3419 children from 328 US and Canadian Get With The Guidelines–Resuscitation sites with an in-hospital cardiac arrest between January 2000 and December 2009. Patients were stratified into 5 patient illness categories: surgical cardiac, medical cardiac, general medical, general surgical, and trauma. Survival to discharge was 27.9%, but only 19.0% of all cardiac arrest patients had favorable neurological outcomes. Between 1 and 15 minutes of CPR, survival decreased linearly by 2.1% per minute, and rates of favorable neurological outcome decreased by 1.2% per minute. Adjusted probability of survival was 41% for CPR duration of 1 to 15 minutes and 12% for >35 minutes. Among survivors, favorable neurological outcome occurred in 70% undergoing <15 minutes of CPR and 60% undergoing CPR >35 minutes. Compared with general medical patients, surgical cardiac patients had the highest adjusted odds ratios for survival and favorable neurological outcomes, 2.5 (95% confidence interval, 1.8–3.4) and 2.7 (95% confidence interval, 2.0–3.9), respectively.

Conclusions—

CPR duration was independently associated with survival to hospital discharge and neurological outcome. Among survivors, neurological outcome was favorable for the majority of patients. Performing CPR for >20 minutes is not futile in some patient illness categories.
Levels of Subjective Globalization: Ideologies, Imaginaries, Ontologies
Authors: Steger Manfred B. , James Paul
Published: January 2013

Abstract

The subjective dimensions of globalization have not received even close to the level of attention that has been paid to the objective dimensions of global interchange and extension. Seeking to rectify this neglect, we argue that the subjective dimensions of globalization can be conceptualized in terms of three dimensions or levels: ideologies, imaginaries, and ontologies. The Occupy Movement in several global locations seeks to challenge global capitalism as the dominant system of economics. At the ideological level, activists connected to Occupy tend to engage in fierce contestation of the global structuring of greed, thus exhibiting clear signs of global rebellion. However, the terms of debate and critique tend to become increasingly uncontested as we go deeper into examining the dominant social imaginary and the ontologies of modern time and space that underpin this general sense of the global. Occupy is clearly an important variant of “justice globalism” that has inspired scores of young activists to protest against increasing inequality and the growing concentration of wealth in the hands of a tiny minority. Still, we suggest that this important alter-globalization movement often works within many of the same subjective frameworks and precepts as the market-globalist world that it criticizes.
New Social Movements and the Egyptian Spring: A Comparative Analysis between the April 6 Movement and the Revolutionary Socialists
Authors: Hafez Bassem Nabil
Published: January 2013

Abstract

In this article I will comparatively analyze the conceptual foundations of two Egyptian protest movements, the April 6 Movement and the Revolutionary Socialists, two prominent instigators of the Egyptian revolution, as part of the global rebellion against the dystopia perceived as the creation of neo-liberalism and globalization. In Egypt, the limitations of conventional opposition led to the mushrooming of New Social Movements (NSMs) over the past decade. The political dynamics since 2000 have yielded, among many, the aforementioned youth movements that represent two different approaches to the rebellion against the dystopia, which speeded up the downfall of Mubarak.