bluuebunny/crossref_metadata_2025 huggingface dataset:
Primary Isolated Lymphoma of the Fourth Ventricle in an Immunocompetent Patient
Authors: Bokhari Rakan , Ghanem Ahmad , Alahwal Mahmoud , Baeesa Saleh
Published: March 2013

Primary central nervous lymphoma (PCNSL) is a rare variant of extranodal non-Hodgkin's lymphoma with a especially poor prognosis. The diagnosis is usually encountered in immunodeficient patients but is also encountered, albeit uncommonly, in the immunocompetent. We present a 50-year-old male who developed signs and symptoms of increased intracranial pressure. Imaging revealed the presence of a fourth ventricle mass with obstructive hydrocephalus. First, the patient underwent emergency endoscopic third ventriculostomy followed, few days later, by complete tumor resection via a posterior fossa craniotomy. Postoperative histopathology revealed the lesion to be a PCNSL. He received adjuvant chemotherapy and radiation and remained with no recurrence on regular imaging studies for 18-month followup. We report herein the fourth case of isolated PCNSL lesion to the fourth ventricle in the literature and provide the rationale for our belief that craniotomy and tumor resection, if feasible, should be the initial line of management in similar cases to relieve hydrocephalus and achieve the diagnosis.
Discretization of Multidimensional Mathematical Equations of Dam Break Phenomena Using a Novel Approach of Finite Volume Method
Authors: Vosoughifar Hamid Reza , Dolatshah Azam , Sadat Shokouhi Seyed Kazem
Published: March 2013

This paper was concerned to simulate both wet and dry bed dam break problems. A high-resolution finite volume method (FVM) was employed to solve the one-dimensional (1D) and two-dimensional (2D) shallow water equations (SWEs) using an unstructured Voronoi mesh grid. In this attempt, the robust local Lax-Friedrichs (LLxF) scheme was used for the calculating of the numerical flux at cells interfaces. The model named V-Break was run under the asymmetry partial and circular dam break conditions and then verified by comparing the model outputs with the documented results. Due to a precise agreement between those output and documented results, the V-Break could be considered as a reliable method for dealing with shallow water (SW) and shock problems, especially those having discontinuities. In addition, statistical observations indicated a good conformity between the V-Break and analytical results clearly.
A New Method for Determining the Nanocrystallite Size Distribution in Systems Where Chemical Reaction between Solid and a Gas Phase Occurs
Authors: Pelka Rafał , Arabczyk Walerian
Published: March 2013

The proposed method, based on measuring the chemical reaction rate in solid phase, is, therefore, limited to such systems where reaction between nanocrystalline materials and a gas phase occurs. Additionally, assumptions of the model of reaction between nanocrystalline materials and a gas phase, where the surface chemical reaction rate is the rate limiting step, are used. As an example of such a reaction, nitriding (with ammonia) of the prereduced industrial iron catalysts for ammonia synthesis of different average crystallite sizes was used. To measure the reaction rate, the differential reactor equipped with systems for thermogravimetric measurements and analysis of the chemical composition of the gas phase was used. The crystallites mass and size distributions for the analyzed samples of catalyst were determined.
Successful Use of Cyclophosphamide as an Add-On Therapy for Multiple Myeloma Patients with Acquired Resistance to Bortezomib or Lenalidomide
Authors: Ito Shigeki , Oyake Tatsuo , Murai Kazunori , Ishida Yoji
Published: March 2013

Novel agents such as thalidomide, lenalidomide, and bortezomib have been shown to possess potent activity against multiple myeloma. However, the treatment strategy for patients who acquired resistance to these agents has not been established. In addition to switching drug classes, intensified treatment strategy, including increase in the dosage of current agents and addition of other agents, may be considered for these patients. We here describe 2 myeloma patients with acquired resistance to bortezomib or lenalidomide, in whom add-on therapy with low-dose cyclophosphamide was effective and tolerable. These cases suggest that add-on therapy with cyclophosphamide is one of the treatment options to overcome resistance to novel agents in patients with multiple myeloma. A larger prospective study is needed to clarify the efficacy and safety of this strategy for novel agent-resistant multiple myeloma.
Study on the Fluidic Component of the Complete Fluidic Sprinkler
Authors: Li Hong , Wang Chao , Chen Chao , Shen Zhenhua
Published: March 2013

The PXH fluidic sprinkler controlled by the outlet clearance is a new type sprinkler which is driven and controlled by the Coanda effect. This paper analyzes the offset jet with control stream in the simplified model. Based on the special design of the fluidic component of the fluidic sprinkler, a control stream coefficient was proposed and the air entrance hole distance was considered as one of the key factors that, influence the offset flow field. Based on the numerical simulations and the experiments, the influences made by different air entrance hole distances, offset ratios, and working pressures on the water-air two-phase flow field of the simplified fluidic component have been studied. The offset distance, the pressure distribution on the offset wall, the yaw angle of the main jet flow and their variations with the pressure, and the structural parameters were obtained. The air velocity variation in the air entrance hole was regarded as the judgment for a complete attachment. Visualization experiments and pressure distribution experiments were carried out and the experimental results show a good agreement with simulation results.
Study on Mixed Solvency Concept in Formulation Development of Aqueous Injection of Poorly Water Soluble Drug
Authors: Solanki Shailendra Singh , Soni Love Kumar , Maheshwari Rajesh Kumar
Published: March 2013

In the present investigation, mixed-solvency approach has been applied for the enhancement of aqueous solubility of a poorly water- soluble drug, zaltoprofen (selected as a model drug), by making blends (keeping total concentrations 40% w/v, constant) of selected water-soluble substances from among the hydrotropes (urea, sodium benzoate, sodium citrate, nicotinamide); water-soluble solids (PEG-4000, PEG-6000); and co-solvents (propylene glycol, glycerine, PEG-200, PEG-400, PEG-600). Aqueous solubility of drug in case of selected blends (12 blends) ranged from 9.091 ± 0.011 mg/ml–43.055 ± 0.14 mg/ml (as compared to the solubility in distilled water 0.072 ± 0.012 mg/ml). The enhancement in the solubility of drug in a mixed solvent containing 10% sodium citrate, 5% sodium benzoate and 25 % S cosolvent (25% S cosolvent contains PEG200, PEG 400, PEG600, Glycerine and Propylene glycol) was more than 600 fold. This proved a synergistic enhancement in solubility of a poorly water-soluble drug due to mixed cosolvent effect. Each solubilized product was characterized by ultraviolet and infrared techniques. Various properties of solution such as pH, viscosity, specific gravity and surface tension were studied. The developed formulation was studied for physical and chemical stability. This mixed solvency shall prove definitely a boon for pharmaceutical industries for the development of dosage form of poorly water soluble drugs.
Endocan in Cancers: A Lesson from a Circulating Dermatan Sulfate Proteoglycan
Authors: Delehedde Maryse , Devenyns Lucie , Maurage Claude-Alain , Vivès Romain R.
Published: March 2013

As most proteoglycans exert their biological activities in the pericellular region, circulating Endocan has appeared since its discovery as an atypical dermatan sulfate proteoglycan, with distinctive structural and functional properties. Endocan is naturally expressed by endothelial cells, highly regulated in presence of proinflammatory and proangiogenic molecules, binds to matrix proteins, growth factors, integrin, and cells, and may be then considered as an accurate marker of endothelial activation. Consequently, Endocan expression has been associated with a growing number of pathological conditions where endothelium gets challenged and notably in highly vascularized cancers. In this context, Endocan has indeed been rapidly emerging as a promising tissue- and blood-based marker of the vascular growth and neoangiogenesis during cancer progression. Furthermore, very recent studies have reported an expression of Endocan by the tumor cells themselves. This highlights Endocan as a multifaceted molecule with a great interest for researchers and clinicians to better understand tumor development, from the bench to the clinics. With promising perspectives of clinical applications, Endocan thus appears as an exciting model for on going and future developments of proteoglycan-based approaches in cancer diagnostics and/or therapy.
Power Line Communications for Smart Grid Applications
Authors: Berger Lars Torsten , Schwager Andreas , Escudero-Garzás J. Joaquín
Published: March 2013

Power line communication, that is, using the electricity infrastructure for data transmission, is experiencing a renaissance in the context ofSmart Grid. Smart Grid objectives include the integration of intermittent renewable energy sources into the electricity supply chain, securing reliable electricity delivery, and using the existing electrical infrastructure more efficiently. This paper surveyspower line communications(PLCs) in the context of Smart Grid. The specificationsG3-PLC,PRIME,HomePlug Green PHY, andHomePlug AV2, and the standardsIEEE 1901/1901.2andITU-T G.hn/G.hnemare discussed.
Globalμ-Stability Analysis for Impulsive Stochastic Neural Networks with Unbounded Mixed Delays
Authors: Yin Lizi , Wang Xinchun
Published: March 2013

We investigate the globalμ-stability in the mean square of impulsive stochastic neural networks with unbounded time-varying delays and continuous distributed delays. By choosing an appropriate Lyapunov-Krasovskii functional, a novel robust stability condition, in the form of linear matrix inequalities, is derived. These sufficient conditions can be tested by MATLAB LMI software packages. The results extend and improve the earlier publication. Two numerical examples are provided to illustrate the effectiveness of the obtained theoretical results.
The Correlation between High-Sensitivity C-Reactive Protein, Matrix Metallopeptidase 9, and Traditional Chinese Medicine Syndrome in Patients with Hypertension
Authors: Wu Aiming , Zhang Dongmei , Gao Yonghong , Lou Lixia , Zhu Haiyan , Chai Limin , Lv Xiying , Sun Yikun , Zhu Lingqun , Wang Shuoren
Published: March 2013

Hypertension is a common disease affecting millions of people throughout the world. Currently, there is a growing interest in the traditional Chinese medicine (TCM) for patients with hypertension mainly due to the personalized therapy of TCM in many countries. Clinical treatment of patients relies on the successful differentiation of a specific TCM syndrome for hypertension. However, it is difficult to understand that TCM syndrome classifications depend on the clinical experience of a TCM practitioner. Therefore, discovering an objective biomarker associated with TCM syndrome may be beneficial for TCM syndrome classifications. This paper focused on high sensitivity C-reactive protein (HCRP), matrix metallopeptidase 9 (MMP9), and TCM syndrome, and aimed to investigate the relationships between TCM syndrome and the two inflammatory biomarkers in patients with essential hypertension. The result showed that both HCRP and MMP9 are positively correlated with syndrome of wind and phlegm turbidity. Detection of the serum levels of HCRP and MMP9 is beneficial for TCM syndrome classification and prediction of cardiovascular and cerebrovascular risk events in hypertensive patients.
The Impact of Bariatric Surgery on Psychological Health
Authors: Kubik Jeremy F. , Gill Richdeep S. , Laffin Michael , Karmali Shahzeer
Published: March 2013

Obesity is associated with a relatively high prevalence of psychopathological conditions, which may have a significant negative impact on the quality of life. Bariatric surgery is an effective intervention in the morbidly obese to achieve marked weight loss and improve physical comorbidities, yet its impact on psychological health has yet to be determined. A review of the literature identified a trend suggesting improvements in psychological health after bariatric surgery. Majority of mental health gain is likely attributed to weight loss and resultant gains in body image, self-esteem, and self-concept; however, other important factors contributing to postoperative mental health include a patient’s sense of taking control of his/her life and support from health care staff. Preoperative psychological health also plays an important role. In addition, the literature suggests similar benefit in the obese pediatric population. However, not all patients report psychological benefits after bariatric surgery. Some patients continue to struggle with weight loss, maintenance and regain, and resulting body image dissatisfaction. Severe preoperative psychopathology and patient expectation that life will dramatically change after surgery can also negatively impact psychological health after surgery. The health care team must address these issues in the perioperative period to maximize mental health gains after surgery.
Uncertainty and the Reform of Elementary Math Education
Authors: Melville Wayne , Kajander Ann , Kerr Donald , Holm Jennifer
Published: March 2013

This paper investigates the notion of uncertainty as elementary teachers engage in conversations intended to develop their understanding and implementation of reform-based mathematics teaching. Using a narrative methodology, several sources of teacher uncertainty are investigated: teaching and learning, the subject, and improving one’s own teaching. The data analysis indicates two important findings. The first is the importance of substantive and syntactic subject knowledge as a necessary foundation for teachers to understand uncertainty in terms that renew their classroom practice. The second is the need to develop and sustain communities in which teachers value opportunities to critique their classroom practices.
Two-Period Inventory Control with Manufacturing and Remanufacturing under Return Compensation Policy
Authors: Sun Xiaochen , Wu Mengmeng , Hu Fei
Published: March 2013

As an effective way of decreasing production cost, remanufacturing has attracted more and more attention from firms. However, it also brings many difficulties to firms, especial when firms remanufacture products which they produce. A primary problem for the case is how to acquire the used product sold by the firm itself. In this paper, we consider a return compensation policy for acquiring used product from customers. Under this policy, the return quantity of used product is a proportion of demand. We study an inventory replenishment and production planning problem for a two-period inventory system with dependent return and demand. We formulate the problem into a three-stage stochastic programming problem, where the firm needs to make decisions on the replenishment quantity of new raw material inventory in each period and the production quantities of manufacturing and remanufacturing ways. We give the optimal production policy of manufacturing and remanufacturing ways for the realized demand and prove the objective function for each stage to be concave in the inventory replenishment quantity. Moreover, we prove that the basic inventory policy is still optimal for each period and give the analytical conditions of the optimal inventory levels which are unrelated to acquisition price. Finally, we investigate numerical studies to analyze managerial insights.
Noise Source Identification of a Ring-Plate Cycloid Reducer Based on Coherence Analysis
Authors: Yang Bing , Liu Yan
Published: March 2013

A ring-plate-type cycloid speed reducer is one of the most important reducers owing to its low volume, compactness, smooth and high performance, and high reliability. The vibration and noise tests of the reducer prototype are completed using the HEAD acoustics multichannel noise test and analysis system. The characteristics of the vibration and noise are obtained based on coherence analysis and the noise sources are identified. The conclusions provide the bases for further noise research and control of the ring-plate-type cycloid reducer.
Two Single-Nucleotide Polymorphisms in ADAM12 Gene Are Associated with Early and Late Radiographic Knee Osteoarthritis in Estonian Population
Authors: Kerna Irina , Kisand Kalle , Tamm Ann E. , Kumm Jaanika , Tamm Agu O.
Published: March 2013

Objectives. To investigate associations of selected single-nucleotide polymorphisms (SNPs) in ADAM12 gene with radiographic knee osteoarthritis (rKOA) in Estonian population. Methods. The rs3740199, rs1871054, rs1278279, and rs1044122 SNPs in ADAM12 gene were genotyped in 438 subjects (303 women) from population-based cohort, aged 32 to 57 (mean 45.4). The rKOA features were evaluated in the tibiofemoral joint (TFJ) and patellofemoral joint. Results. The early rKOA was found in 51.4% of investigated subjects (72% women) and 12.3% of participants (63% women) had advanced stage of diseases. The A allele of synonymous SNP rs1044122 was associated with early rKOA in TFJ, predominantly with the presence of osteophytes in females (OR 1.57; 95% CI 1.08–2.29, ). The C allele of intron polymorphism rs1871054 carried risk for advanced rKOA, mostly to osteophyte formation in TFJ in males (OR 3.03; 95% CI 1.11–7.53, ). Also the CCAA haplotype of ADAM12 was associated with osteophytosis, again mostly in TFJ in males (). For rs3740199 and rs1278279, no statistically significant associations were observed. Conclusion.  ADAM12 gene variants are related to rKOA risk during the early and late stages of diseases. The genetic risk seems to be predominantly associated with the appearance of osteophytes—a marker of bone remodelling and neochondrogenesis.
Bifurcation of Positive Solutions for a Class of Boundary Value Problems of Fractional Differential Inclusions
Authors: Liu Yansheng , Yu Huimin
Published: March 2013

Using Krein-Rutman theorem, topological degree theory, and bifurcation techniques, this paper investigates the existence of positive solutions for a class of boundary value problems of fractional differential inclusions.
Intersection-Soft Filters inR0-Algebras
Authors: Jun Young Bae , Ahn Sun Shin , Lee Kyoung Ja
Published: March 2013

The notions of (strong) intersection-soft filters inR0-algebras are introduced, and related properties are investigated. Characterizations of a (strong) intersection-soft filter are established, and a new intersection-soft filter from old one is constructed. A condition for an intersection-soft filter to be strong is given, and an extension property of a strong intersection-soft filter is established.
Planning Horizon for Production Inventory Models with Production Rate Dependent on Demand and Inventory Level
Authors: Lin Jennifer , Chao Henry C. J. , Julian Peterson
Published: March 2013

This paper discusses why the selection of a finite planning horizon is preferable to an infinite one for a replenishment policy of production inventory models. In a production inventory model, the production rate is dependent on both the demand rate and the inventory level. When there is an exponentially decreasing demand, the application of an infinite planning horizon model is not suitable. The emphasis of this paper is threefold. First, while pointing out questionable results from a previous study, we propose a corrected infinite planning horizon inventory model for the first replenishment cycle. Second, while investigating the optimal solution for the minimization problem, we found that the infinite planning horizon should not be applied when dealing with an exponentially decreasing demand. Third, we developed a new production inventory model under a finite planning horizon for practitioners. Numerical examples are provided to support our findings.
Robustl2−l∞Filtering for Takagi-Sugeno Fuzzy Systems with Norm-Bounded Uncertainties
Authors: Li Wenbai , Xu Yu , Li Huaizhong
Published: March 2013

We study the filter design problem for Takagi-Sugeno fuzzy systems which are subject to norm-bounded uncertainties in each subsystem. As we know that the Takagi-Sugeno fuzzy linear systems can be used to represent smooth nonlinear systems, the studied plants can also be uncertain complex systems. We suppose to design a filter with the order of the original system which is also dependent on the normalized fuzzy-weighting function; that is, the filter is also a Takagi-Sugeno fuzzy filter. With the augmentation technique, an uncertain filtering error system can be obtained and the system matrices in the filtering error system are reorganized into two categories (without uncertainties and with uncertainties). For the filtering error system, we have two objectives. (1) The first one is that the filtering error system should be robust stable; that is, the filtering error system is stable though there are uncertainties in the original system. (2) The second one is that the robust energy-to-peak performance should be guaranteed. With the well-known Finsler’s lemma, we provide the conditions for the robust energy-to-peak performance of the filtering error system in which three slack matrices are introduced. Finally, a numerical example is used to show the effectiveness of the proposed design methodology.
Genetic Susceptibility to Triple-Negative Breast Cancer
Authors: Stevens Kristen N. , Vachon Celine M. , Couch Fergus J.
Published: March 2013

Triple-negative breast cancers (TNBC), defined by the absence of estrogen receptor, progesterone receptor, and HER-2 expression, account for 12% to 24% of all breast cancers. TNBC is associated with early recurrence of disease and poor outcome. Germline mutations in the BRCA1 and BRCA2 breast cancer susceptibility genes have been associated with up to 15% of TNBC, and TNBC accounts for 70% of breast tumors arising in BRCA1 mutation carriers and 16% to 23% of breast tumors in BRCA2 carriers. Whether germline mutations in other breast cancer susceptibility genes also predispose to TNBC remains to be determined. Common variation in a subset of the 72 known breast cancer susceptibility loci identified through genome-wide association studies and other large-scale genotyping efforts have also been associated with risk of TNBC (TOX3, ESR1, RAD51L1, TERT, 19p13.1, 20q11, MDM4, 2p24.1, and FTO). Furthermore, variation in the 19p13.1 locus and the MDM4 locus has been associated with TNBC, but not other forms of breast cancer, suggesting that these are TNBC-specific loci. Thus, TNBC can be distinguished from other breast cancer subtypes by a unique pattern of common and rare germline predisposition alleles. Additional efforts to combine genetic and epidemiologic data are needed to better understand the etiology of this aggressive form of breast cancer, to identify prevention and therapeutic targets, and to impact clinical practice through the development of risk prediction models. Cancer Res; 73(7); 2025–30. ©2012 AACR.
ATF3 Suppresses Metastasis of Bladder Cancer by Regulating Gelsolin-Mediated Remodeling of the Actin Cytoskeleton
Authors: Yuan Xiangliang , Yu Liang , Li Junhua , Xie Guohua , Rong Tingting , Zhang Liang , Chen Jianhua , Meng Qiaohong , Irving Aaron T. , Wang Die , Williams Elizabeth D. , Liu Jun-Ping , Sadler Anthony J. , Williams Bryan R.G. , Shen Lisong , Xu Dakang
Published: March 2013

Bladder cancer is associated with high recurrence and mortality rates due to metastasis. The elucidation of metastasis suppressors may offer therapeutic opportunities if their mechanisms of action can be elucidated and tractably exploited. In this study, we investigated the clinical and functional significance of the transcription factor activating transcription factor 3 (ATF3) in bladder cancer metastasis. Gene expression analysis revealed that decreased ATF3 was associated with bladder cancer progression and reduced survival of patients with bladder cancer. Correspondingly, ATF3 overexpression in highly metastatic bladder cancer cells decreased migration in vitro and experimental metastasis in vivo. Conversely, ATF3 silencing increased the migration of bladder cancer cells with limited metastatic capability in the absence of any effect on proliferation. In keeping with their increased motility, metastatic bladder cancer cells had increased numbers of actin filaments. Moreover, ATF3 expression correlated with expression of the actin filament severing protein gelsolin (GSN). Mechanistic studies revealed that ATF3 upregulated GSN, whereas ATF3 silencing reduced GSN levels, concomitant with alterations in the actin cytoskeleton. We identified six ATF3 regulatory elements in the first intron of the GSN gene confirmed by chromatin immunoprecipitation analysis. Critically, GSN expression reversed the metastatic capacity of bladder cancer cells with diminished levels of ATF3. Taken together, our results indicate that ATF3 suppresses metastasis of bladder cancer cells, at least in part through the upregulation of GSN-mediated actin remodeling. These findings suggest ATF3 coupled with GSN as prognostic markers for bladder cancer metastasis. Cancer Res; 73(12); 3625–37. ©2013 AACR.
Interleukin-1β Promotes Skeletal Colonization and Progression of Metastatic Prostate Cancer Cells with Neuroendocrine Features
Authors: Liu Qingxin , Russell Mike R. , Shahriari Kristina , Jernigan Danielle L. , Lioni Mercedes I. , Garcia Fernando U. , Fatatis Alessandro
Published: March 2013

Despite the progress made in the early detection and treatment of prostate adenocarcinoma, the metastatic lesions from this tumor are incurable. We used genome-wide expression analysis of human prostate cancer cells with different metastatic behavior in animal models to reveal that bone-tropic phenotypes upregulate three genes encoding for the cytokine interleukin-1β (IL-1β), the chemokine CXCL6 (GCP-2), and the protease inhibitor elafin (PI3). The Oncomine database revealed that these three genes are significantly upregulated in human prostate cancer versus normal tissue and correlate with Gleason scores ≥7. This correlation was further validated for IL-1β by immunodetection in prostate tissue arrays. Our study also shows that the exogenous overexpression of IL-1β in nonmetastatic cancer cells promotes their growth into large skeletal lesions in mice, whereas its knockdown significantly impairs the bone progression of highly metastatic cells. In addition, IL-1β secreted by metastatic cells induced the overexpression of COX-2 (PTGS2) in human bone mesenchymal cells treated with conditioned media from bone metastatic prostate cancer cells. Finally, we inspected human tissue specimens from skeletal metastases and detected prostate cancer cells positive for both IL-1β and synaptophysin while concurrently lacking prostate-specific antigen (PSA, KLK3) expression. Collectively, these findings indicate that IL-1β supports the skeletal colonization and metastatic progression of prostate cancer cells with an acquired neuroendocrine phenotype. Cancer Res; 73(11); 3297–305. ©2013 AACR.
Temozolomide-Mediated DNA Methylation in Human Myeloid Precursor Cells: Differential Involvement of Intrinsic and Extrinsic Apoptotic Pathways
Authors: Wang Haiyan , Cai Shanbao , Ernstberger Aaron , Bailey Barbara J. , Wang Michael Z. , Cai Wenjing , Goebel W. Scott , Czader Magdalena B. , Crean Colin , Suvannasankha Attaya , Shokolenkoc Inna , Wilson Glenn L. , Baluyut Arthur R. , Mayo Lindsey D. , Pollok Karen E.
Published: March 2013

Purpose: An understanding of how hematopoietic cells respond to therapy that causes myelosuppression will help develop approaches to prevent this potentially life-threatening toxicity. The goal of this study was to determine how human myeloid precursor cells respond to temozolomide (TMZ)-induced DNA damage.

Experimental Design: We developed an ex vivo primary human myeloid precursor cells model system to investigate the involvement of cell-death pathways using a known myelosuppressive regimen of O6-benzylguanine (6BG) and TMZ.

Results: Exposure to 6BG/TMZ led to increases in p53, p21, γ-H2AX, and mitochondrial DNA damage. Increases in mitochondrial membrane depolarization correlated with increased caspase-9 and -3 activities following 6BG/TMZ treatment. These events correlated with decreases in activated AKT, downregulation of the DNA repair protein O6-methylguanine–DNA methyltransferase (MGMT), and increased cell death. During myeloid precursor cell expansion, FAS/CD95/APO1(FAS) expression increased over time and was present on approximately 100% of the cells following exposure to 6BG/TMZ. Although c-flipshort, an endogenous inhibitor of FAS-mediated signaling, was decreased in 6BG/TMZ–treated versus control, 6BG-, or TMZ alone–treated cells, there were no changes in caspase-8 activity. In addition, there were no changes in the extent of cell death in myeloid precursor cells exposed to 6BG/TMZ in the presence of neutralizing or agonistic anti-FAS antibodies, indicating that FAS-mediated signaling was not operative.

Conclusions: In human myeloid precursor cells, 6BG/TMZ–initiated apoptosis occurred by intrinsic, mitochondrial-mediated and not extrinsic, FAS-mediated apoptosis. Human myeloid precursor cells represent a clinically relevant model system for gaining insight into how hematopoietic cells respond to chemotherapeutics and offer an approach for selecting effective chemotherapeutic regimens with limited hematopoietic toxicity. Clin Cancer Res; 19(10); 2699–709. ©2013 AACR.
Infection and Cancer: Revaluation of the Hygiene Hypothesis
Authors: Oikonomopoulou Katerina , Brinc Davor , Kyriacou Kyriacos , Diamandis Eleftherios P.
Published: March 2013

Several studies have shown that persistent infections and inflammation can favor carcinogenesis. At the same time, certain types of pathogens and antitumor immune responses can decrease the risk of tumorigenesis or lead to cancer regression. Infectious agents and their products can orchestrate a wide range of host immune responses, through which they may positively or negatively modulate cancer development and/or progression. The factors that direct this dichotomous influence of infection-mediated immunity on carcinogenesis are not well understood. Even though not universal, several previous reports have investigated the inverse link of pathogen-induced “benign” inflammation to carcinogenesis and various other pathologies, ranging from autoimmune diseases to allergy and cancer. Several models and ideas are discussed in this review, including the impact of decreased exposure to pathogens, as well as the influence of pathogen load, the timing of infection, and the type of instigated immune response on carcinogenesis. These phenomena should guide future investigations into identifying novel targets within the microbial and host proteome, which will assist in the development of cancer therapeutics and vaccine remedies, analogous to earlier efforts based on helminthic components for the prevention and/or treatment of several pathologies. Clin Cancer Res; 19(11); 2834–41. ©2013 AACR.
Discovery of a Novel Orally Active Small-Molecule gp130 Inhibitor for the Treatment of Ovarian Cancer
Authors: Xu Shili , Grande Fedora , Garofalo Antonio , Neamati Nouri
Published: March 2013

Interleukin (IL)-6 and Stat3 play key roles in ovarian cancer progression. However, the role of glycoprotein 130 (gp130), the signal transducer of this signaling axis, is not well-established. Currently, there are no small-molecule inhibitors of gp130 under clinical development. In this study, we show that gp130 is an attractive drug target in ovarian cancer due to its role in promoting cancer progression via the activation of its downstream Stat3 signaling. We also present preclinical studies of SC144, the first-in-class orally active small-molecule gp130 inhibitor. SC144 shows greater potency in human ovarian cancer cell lines than in normal epithelial cells. SC144 binds gp130, induces gp130 phosphorylation (S782) and deglycosylation, abrogates Stat3 phosphorylation and nuclear translocation, and further inhibits the expression of downstream target genes. In addition, SC144 shows potent inhibition of gp130 ligand–triggered signaling. Oral administration of SC144 delays tumor growth in a mouse xenograft model of human ovarian cancer without significant toxicity to normal tissues. Mol Cancer Ther; 12(6); 937–49. ©2013 AACR.
Discovery of the Novel mTOR Inhibitor and Its Antitumor Activities In Vitro and In Vivo
Authors: Xie Hua , Lee Mee-Hyun , Zhu Feng , Reddy Kanamata , Huang Zunnan , Kim Dong Joon , Li Yan , Peng Cong , Lim Do Young , Kang Soouk , Jung Sung Keun , Li Xiang , Li Haitao , Ma Weiya , Lubet Ronald A. , Ding Jian , Bode Ann M. , Dong Zigang
Published: March 2013

The phosphoinositide 3-kinase (PI3-K)/Akt and mTOR signaling pathway plays a critical role in cell survival and proliferation and is often aberrantly activated in many types of cancer. The mTOR kinase protein, one of the key molecules in this pathway, has been shown to be an important target for cancer therapy. In the present study, a ligand docking method was used to screen for novel scaffold mTOR inhibitors. Sixty thousand compounds in the Natural Product Database were screened against the mTOR homologous structure, and 13 commercially available compounds listed in the top-ranked 100 compounds were selected for further examination. Compound [(E)-3-(4-(benzo[d][1,3]dioxol-5-yl)-2-oxobut-3-en-1-yl)- 3-hydroxyindolin-2-one; designated herein as 3HOI-BA-01] was then selected for further study of its antitumor activity. An in vitro study has shown that 3HOI-BA-01 inhibited mTOR kinase activity in a dose-dependent manner by directly binding with mTOR. In a panel of non–small cell lung cancer cells, the compound also attenuated mTOR downstream signaling, including the phosphorylation of p70S6K, S6, and Akt, resulting in G1 cell-cycle arrest and growth inhibition. Results of an in vivo study have shown that intraperitoneal injection of 3HOI-BA-01 in A549 lung tumor–bearing mice effectively suppressed cancer growth without affecting the body weight of the mice. The expression of downstream signaling molecules in the mTOR pathway in tumor tissues was also reduced after 3HOI-BA-01 treatment. Taken together, we identified 3HOI-BA-01 as a novel and effective mTOR inhibitor. Mol Cancer Ther; 12(6); 950–8. ©2013 AACR.
Activation of the FGF2-FGFR1 Autocrine Pathway: A Novel Mechanism of Acquired Resistance to Gefitinib in NSCLC
Authors: Terai Hideki , Soejima Kenzo , Yasuda Hiroyuki , Nakayama Sohei , Hamamoto Junko , Arai Daisuke , Ishioka Kota , Ohgino Keiko , Ikemura Shinnosuke , Sato Takashi , Yoda Satoshi , Satomi Ryosuke , Naoki Katsuhiko , Betsuyaku Tomoko
Published: March 2013

Patients with non-small cell lung cancer (NSCLC) that harbors epidermal growth factor receptor (EGFR) mutations initially respond to EGFR-tyrosine kinase inhibitors (TKI) but eventually experience relapse. Acquired resistance to EGFR-TKIs is strongly associated with patient mortality. Thus, elucidation of the mechanism of acquired resistance to EGFR-TKIs is of great importance. In this study, gefitinib-resistant cell line models were established by long-term exposure to gefitinib using the gefitinib-sensitive lung cancer cell lines, PC9 and HCC827. Expression analyses indicated that both FGFR1 and FGF2 were increased in PC9 gefitinib-resistant (PC9 GR) cells as compared with PC9 naïve (PC9 na) cells. Importantly, proliferation of gefitinib-resistant cells was dependent on the FGF2 -FGFR1 pathway. Mechanistically, inhibition of either FGF2 or FGFR1 by siRNA or FGFR inhibitor (PD173074) restored gefitinib sensitivity in PC9 GR cells. These data suggest that FGF2 -FGFR1 activation through an autocrine loop is a novel mechanism of acquired resistance to EGFR-TKIs. Mol Cancer Res; 11(7); 759–67. ©2013 AACR.
Parenteral anticoagulants in heart disease: Current status and perspectives (Section II)
Authors: Husted Steen , Wallentin Lars , Andreotti Felicita , Arnesen Harald , Bachmann Fedor , Baigent Colin , Huber Kurt , Jespersen Jørgen , Kristensen Steen , Lip Gregory Y. H. , Morais João , Rasmussen Lars , Siegbahn Agneta , Verheugt Freek W. A. , Weitz Jeffrey I. , De Caterina Raffaele
Published: March 2013

Anticoagulants are a mainstay of cardiovascular therapy, and parenteral anticoagulants have widespread use in cardiology, especially in acute situations. Parenteral anticoagulants include unfractionated heparin, low-molecular-weight heparins, the synthetic pentasaccharides fondaparinux, idraparinux and idrabiotaparinux, and parenteral direct thrombin inhibitors. The several shortcomings of unfractionated heparin and of low-molecular-weight heparins have prompted the development of the other newer agents. Here we review the mechanisms of action, pharmacological properties and side effects of parenteral anticoagulants used in the management of coronary heart disease treated with or without percutaneous coronary interventions, cardioversion for atrial fibrillation, and prosthetic heart valves and valve repair. Using an evidence-based approach, we describe the results of completed clinical trials, highlight ongoing research with currently available agents, and recommend therapeutic options for specific heart diseases.
The physiological and pathophysiological roles of platelet CLEC-2
Authors: Langan Stacey A. , Nash Gerard B. , Watson Steve P. , Navarro-Núñez Leyre
Published: March 2013

CLEC-2 is a C-type lectin receptor which is highly expressed on platelets but also found at low levels on different immune cells. CLEC-2 elicits powerful platelet activation upon engagement by its endogenous ligand, the mucin-type glycoprotein podoplanin. Podoplanin is expressed in a variety of tissues, including lymphatic endothelial cells, kidney podocytes, type I lung epithelial cells, lymph node stromal cells and the choroid plexus epithelium. Animal models have shown that the correct separation of the lymphatic and blood vasculatures during embryonic development is dependent on CLEC-2-mediated platelet activation. Additionally, podoplanin-deficient mice show abnormalities in heart, lungs, and lymphoid tissues, whereas absence of CLEC-2 affects brain development. This review summarises the current understanding of the molecular pathways regulating CLEC-2 and podoplanin function and suggests other physiological and pathological processes where this molecular interaction might exert crucial roles.
Prognostic Value of Cardiac Time Intervals by Tissue Doppler Imaging M-Mode in Patients With Acute ST-Segment–Elevation Myocardial Infarction Treated With Primary Percutaneous Coronary Intervention
Authors: Biering-Sørensen Tor , Mogelvang Rasmus , Søgaard Peter , Pedersen Sune H. , Galatius Søren , Jørgensen Peter Godsk , Jensen Jan Skov
Published: March 2013

Background—

Color tissue Doppler imaging M-mode through the mitral leaflet is an easy and precise method to estimate all cardiac time intervals from 1 cardiac cycle and thereby obtain the myocardial performance index (MPI). However, the prognostic value of the cardiac time intervals and the MPI assessed by color tissue Doppler imaging M-mode through the mitral leaflet in patients with ST-segment–elevation myocardial infarction (MI) is unknown.

Methods and Results—

In total, 391 patients were admitted with an ST-segment–elevation MI, treated with primary percutaneous coronary intervention, and examined by echocardiography a median of 2 days after the ST-segment–elevation MI. Outcome was assessed according to death (n=33), hospitalization with heart failure (n=53), or new MI (n=25). Follow-up time was a median of 25 months. The population was stratified according to tertiles of the MPI. The risk of new MI, being admitted with congestive heart failure or death, increased with increasing tertile of MPI, being ≈3 times as high for the third tertile compared with the first tertile (hazard ratio, 2.8; 95% confidence interval, 1.7–4.7;
P
<0.001). MPI provided independent prognostic information in a multivariable Cox regression model adjusted for age, sex, previous MI, peak troponin, and systolic and diastolic echocardiographic parameters, with a hazard ratio of 1.24 (
P
=0.005) for the combined end point per each 0.1 increase in MPI.

Conclusions—

MPI assessed by tissue Doppler imaging M-mode is a simple and reproducible measure that provides independent prognostic information, regardless of rhythm, incremental to conventional and novel echocardiographic parameters of systolic and diastolic function in patients with ST-segment–elevation MI treated with primary percutaneous coronary intervention.
K
ATP
Channels and Cardiovascular Disease
Authors: Nichols Colin G. , Singh Gautam K. , Grange Dorothy K.
Published: March 2013

ATP-sensitive potassium (K
ATP
) channels were first discovered in the heart 30 years ago. Reconstitution of K
ATP
channel activity by coexpression of members of the pore-forming inward rectifier gene family (Kir6.1,
KCNJ8
, and Kir6.2
KCNJ11
) with sulfonylurea receptors (SUR1,
ABCC8
, and SUR2,
ABCC9
) of the ABCC protein subfamily has led to the elucidation of many details of channel gating and pore properties. In addition, the essential roles of Kir6.x and SURx subunits in generating cardiac and vascular K
ATP

2

and the detrimental consequences of genetic deletions or mutations in mice have been recognized. However, despite this extensive body of knowledge, there has been a paucity of defined roles of K
ATP
subunits in human cardiovascular diseases, although there are reports of association of a single Kir6.1 variant with the J-wave syndrome in the ECG, and 2 isolated studies have reported association of loss of function mutations in SUR2 with atrial fibrillation and heart failure. Two new studies convincingly demonstrate that mutations in the SUR2 gene are associated with Cantu syndrome, a complex multi-organ disorder characterized by hypertrichosis, craniofacial dysmorphology, osteochondrodysplasia, patent ductus arteriosus, cardiomegaly, pericardial effusion, and lymphoedema. This realization of previously unconsidered consequences provides significant insight into the roles of the K
ATP
channel in the cardiovascular system and suggests novel therapeutic possibilities.
Type 5 Adenylyl Cyclase Increases Oxidative Stress by Transcriptional Regulation of Manganese Superoxide Dismutase via the SIRT1/FoxO3a Pathway
Authors: Lai Lo , Yan Lin , Gao Shumin , Hu Che-Lin , Ge Hui , Davidow Amy , Park Misun , Bravo Claudio , Iwatsubo Kousaku , Ishikawa Yoshihiro , Auwerx Johan , Sinclair David A. , Vatner Stephen F. , Vatner Dorothy E.
Published: March 2013

Background—

For reasons that remain unclear, whether type 5 adenylyl cyclase (AC5), 1 of 2 major AC isoforms in heart, is protective or deleterious in response to cardiac stress is controversial. To reconcile this controversy we examined the cardiomyopathy induced by chronic isoproterenol in AC5 transgenic (Tg) mice and the signaling mechanisms involved.

Methods and Results—

Chronic isoproterenol increased oxidative stress and induced more severe cardiomyopathy in AC5 Tg, as left ventricular ejection fraction fell 1.9-fold more than wild type, along with greater left ventricular dilation and increased fibrosis, apoptosis, and hypertrophy. Oxidative stress induced by chronic isoproterenol, detected by 8-OhDG was 15% greater,
P
=0.007, in AC5 Tg hearts, whereas protein expression of manganese superoxide dismutase (MnSOD) was reduced by 38%, indicating that the susceptibility of AC5 Tg to cardiomyopathy may be attributable to decreased MnSOD expression. Consistent with this, susceptibility of the AC5 Tg to cardiomyopathy was suppressed by overexpression of MnSOD, whereas protection afforded by the AC5 knockout (KO) was lost in AC5 KO×MnSOD heterozyous KO mice. Elevation of MnSOD was eliminated by both sirtuin and MEK inhibitors, suggesting both the SIRT1/FoxO3a and MEK/ERK pathway are involved in MnSOD regulation by AC5.

Conclusions—

Overexpression of AC5 exacerbates the cardiomyopathy induced by chronic catecholamine stress by altering regulation of SIRT1/FoxO3a, MEK/ERK, and MnSOD, resulting in oxidative stress intolerance, thereby shedding light on new approaches for treatment of heart failure.
Immigrant Unionization through the Great Recession
Authors: Catron Peter
Published: March 2013

Previous research has found that in recent years immigrants had a higher propensity to unionize than did native-born workers. However, little research shows that historically marginalized immigrant workers are able to maintain newly acquired union jobs, especially during times unfavorable to unionization more generally. This comment focuses on immigrant unionization during the Great Recession of 2008 to determine whether inroads that immigrants made through organizing were maintained in hostile union environments. Using the Current Population Survey (CPS), I extend Rosenfeld and Kleykamp’s (2009) models for Hispanic unionization (which end in 2007) through the recent downturn and beyond. I find that Hispanic immigrants, who held higher odds of union entry or membership in Rosenfeld and Kleykamp’s pre-recession analysis, lost union jobs at an increased rate during the Great Recession compared with native-born white workers. These effects for Hispanic immigrants filtered throughout various subcategories and control variables, including years since entry, citizenship status, and nationality. These results are likely not due to immigrants’ unfavorable labor market allocation, and to some degree undercut the hopes of those who view immigrants as the key to organized labor’s future and organized labor as the key to immigrant prosperity.
Race, Legality, and the Social Policy Consequences of Anti-Immigration Mobilization
Authors: Brown Hana E.
Published: March 2013

With the dramatic rise in the U.S. Hispanic population, scholars have struggled to explain how race affects welfare state development beyond the Black-White divide. This article uses a comparative analysis of welfare reforms in California and Arizona to examine how anti-Hispanic stereotypes affect social policy formation. Drawing on interviews, archival materials, and newspaper content analysis, I find that animus toward Hispanics is mobilized through two collective action frames: a legality frame and a racial frame. The legality frame lauds the contributions of documented noncitizens while demonizing illegal immigrants. The racial frame celebrates the moral worth of White citizens and uses explicit racial language to deride Hispanics as undeserving. These subtle differences in racialization and worth attribution create divergent political opportunities for welfare policy. When advocates employ the legality frame, they create openings for rights claims by documented noncitizens. Use of the racial frame, however, dampens cross-racial mobilization and effective claims-making for expansive welfare policies. These findings help to explain why the relationship between race and welfare policy is less predictable for Hispanics than for Blacks. They also reveal surprising ways in which race and immigration affect contemporary politics and political mobilization.