bluuebunny/crossref_metadata_2025 huggingface dataset:
Patterns of Exposure to Multiple Metals and Associations with Neurodevelopment of Preschool Children from Montevideo, Uruguay
Authors: Kordas Katarzyna , Ardoino Graciela , Coffman Donna L. , Queirolo Elena I. , Ciccariello Daniela , Mañay Nelly , Ettinger Adrienne S.
Published: January 2015

While it is known that toxic metals contribute individually to child cognitive and behavioral deficits, we still know little about the effects of exposure to multiple metals, particularly when exposures are low. We studied the association between children’s blood lead and hair arsenic, cadmium, and manganese and their performance on the Bayley Scales of Infant Development III. Ninety-two preschool children (age 13–42 months) from Montevideo, Uruguay, provided a hair sample and 78 had a blood lead level (BLL) measurement. Using latent class analysis (LCA), we identified four groups of exposure based on metal concentrations: (1) low metals, (2) low-to-moderate metals, (3) high lead and cadmium, and (4) high metals. Using the four-group exposure variable as the main predictor, and fitting raw scores on the cognitive, receptive vocabulary, and expressive vocabulary scales as dependent variables, both complete-case and multiple imputation (MI) analyses were conducted. We found no association between multiple-metal exposures and neurodevelopment in covariate-adjusted models. This study demonstrates the use of LCA together with MI to determine patterns of exposure to multiple toxic metals and relate these to child neurodevelopment. However, because the overall study population was small, other studies with larger sample sizes are needed to investigate these associations.
Microbe‐Assisted Synthesis and Luminescence Properties of Monodispersed Tb3+‐Doped ZnS Nanocrystals
Authors: Liang Zhanguo , Mu Jun , Han Lei , Yu Hongquan
Published: January 2015

Tb3+‐doped zinc sulfide (ZnS:Tb3+) nanocrystals were synthesized by spray precipitation with sulfate‐reducing bacterial (SRB) culture at room temperature. The morphology of the SRB and ZnS:Tb3+ nanocrystals was examined by scanning electron microscopy, and the ZnS:Tb3+ nanocrystals were characterized by X‐ray diffractometry and photoluminescence (PL) spectroscopy. The PL mechanism of ZnS:Tb3+ nanocrystals was further analyzed, and the effects of Tb3+ ion concentration on the luminescence properties of ZnS:Tb3+ nanocrystals were studied. ZnS:Tb3+ nanocrystals showed a sphalerite phase, and the prepared ZnS:Tb3+ nanocrystals had high luminescence intensity under excitation at 369 nm. The main peak position of the absorption spectra positively blueshifted with increasing concentrations of Tb3+ dopant. Based on the strength of the peak of the excitation and emission spectra, we inferred that the optimum concentration of the Tb3+ dopant is 5 mol%. Four main emission peaks were obtained under excitation at 369 nm:489 nm (5D4→7F6), 545 nm (5D4→7F5), 594 nm (5D4→7F4), and 625 nm (5D4→7F3). Our findings suggest that nanocrystals have potential applications in photoelectronic devices and biomarkers.
Obstacle Avoidance Algorithm for 7-DOF Redundant Anthropomorphic Arm
Authors: Shen Haoyu , Wu Hongtao , Chen Bai , Jiang Yanjie , Yan Cheng
Published: January 2015

To deal with the problem of obstacle avoidance for redundant robots, an obstacle avoidance algorithm based on the internal motion of the 7-DOF redundant anthropomorphic arm is presented. The motion of that critical points move away from the closest points on the obstacles is defined as obstacle avoiding motion. Two transitioning variables were used to make a smooth, continuous transition between the primary and the secondary tasks. Using this approach, the robot can get the target configuration while avoiding the obstacles. Finally, the validity of the obstacle avoidance algorithm based on transitioning between tasks is manifested by simulation. The results show that, for the obstacle avoiding problem, the redundant robot not only can realize the obstacle avoidance, but also prevents the conflict between tasks by the proposed approach.
Entropy Measures for Interval-Valued Intuitionistic Fuzzy Sets and Their Application in Group Decision-Making
Authors: Wei Cuiping , Zhang Yuzhong
Published: January 2015

Entropy measure is an important topic in the fuzzy set theory and has been investigated by many researchers from different points of view. In this paper, two new entropy measures based on the cosine function are proposed for intuitionistic fuzzy sets and interval-valued intuitionistic fuzzy sets. According to the features of the cosine function, the general forms of these two kinds of entropy measures are presented. Compared with the existing ones, the proposed entropy measures can overcome some shortcomings and be used to measure both fuzziness and intuitionism of these two fuzzy sets; as a result, the uncertain information of which can be described more sufficiently. These entropy measures have been applied to assess the experts’ weights and to solve multicriteria fuzzy group decision-making problems.
Anticytotoxic T-Lymphocyte Antigen-4 Induced Autoimmune Hypophysitis: A Case Report and Literature Review
Authors: Majchel Deborah , Korytkowski Mary T.
Published: January 2015

Objective. We describe a case of autoimmune hypophysitis induced by the anticytotoxic T-lymphocyte antigen-4 (CTLA-4) agent, ipilimumab.Methods. Case presentation and review of the literature.Results. Autoimmune hypophysitis, a previously described rare disorder, is being recognized more frequently as a side effect of novel immunomodulatory agents used in the treatment of malignancies such as melanoma. CTLA-4 agents are associated with immune-related adverse effects (irAE) which occur as a result of activation (or lack of inactivation) of the immune response. This impacts not only malignant cells but also different host organ-systems. Autoimmune hypophysitis is one of several endocrinopathies associated with these agents.Conclusion. It is important that endocrinologists become familiar with the endocrinopathies, such as autoimmune hypophysitis, associated with new immunomodulator agents which are being used with increasing frequency to treat a variety of malignancies.
The Evaluation of Osseointegration of Dental Implant Surface with Different Size of TiO2 Nanotube in Rats
Authors: Yi Young-Ah , Park Young-Bum , Choi Hyunmin , Lee Keun-Woo , Kim Sun-Jai , Kim Kwang-Mahn , Oh Seunghan , Shim June-Sung
Published: January 2015

With the development of nanotechnology, many researches have shown that nanometer‐scaled materials especially
TiO2 nanotube have a positive effect on cellular behavior and surface characteristics of implant, which are considered
to be crucial factors in osseointegration. However, it has not yet been verified which nanotube size is effective in osseointegration in vivo.
The aim of this study was to evaluate the effect of implant surface‐treated with different size of TiO2 nanotubes on osseointegration in rat femur. The customized implants (threaded and nonthreaded type), surface‐treated with different diameter of TiO2 nanotubes (30 nm, 50 nm, 70 nm, and 100 nm nanotube), were placed on both sides of the femur of 50 male Sprague‐Dawley rats (6 weeks old). Rats were sacrificed at 2 and 6 weeks following surgery; then the specimens were collected by perfusion fixation and the osseointegration of implants was evaluated by radiographic and histologic analyses and removal torque value test. The mean of bone area (%) and the mean of removal torque were different in each group, indicating that the difference in TiO2 nanotube size may influence new bone formation and osseointegration in rats.
Mango Fruit Extracts Differentially Affect Proliferation and Intracellular Calcium Signalling in MCF-7 Human Breast Cancer Cells
Authors: Taing Meng-Wong , Pierson Jean-Thomas , Shaw Paul N. , Dietzgen Ralf G. , Roberts-Thomson Sarah J. , Gidley Michael J. , Monteith Gregory R.
Published: January 2015

The assessment of human cancer cell proliferation is a common approach in identifying plant extracts that have potential bioactive effects. In this study, we tested the hypothesis that methanolic extracts of peel and flesh from three archetypal mango cultivars, Irwin (IW), Nam Doc Mai (NDM), and Kensington Pride (KP), differentially affect proliferation, extracellular signal-regulated kinase (ERK) activity, and intracellular calcium ([Ca2+]I) signalling in MCF-7 human breast cancer cells. Mango flesh extracts from all three cultivars did not inhibit cell growth, and of the peel extracts only NDM reduced MCF-7 cell proliferation. Mango cultivar peel and flesh extracts did not significantly change ERK phosphorylation compared to controls; however, some reduced relative maximal peak[Ca2+]Iafter adenosine triphosphate stimulation, with NDM peel extract having the greatest effect among the treatments. Our results identify mango interfruit and intrafruit (peel and flesh) extract variability in antiproliferative effects and[Ca2+]Isignalling in MCF-7 breast cancer cells and highlight that parts of the fruit (such as peel and flesh) and cultivar differences are important factors to consider when assessing potential chemopreventive bioactive compounds in plants extracts.
NLRP3 Inflammasome: Activation and Regulation in Age‐Related Macular Degeneration
Authors: Gao Jiangyuan , Liu Ruozhou Tom , Cao Sijia , Cui Jing Z. , Wang Aikun , To Eleanor , Matsubara Joanne A.
Published: January 2015

Age‐related macular degeneration (AMD) is the leading cause of legal blindness in the elderly in industrialized countries. AMD is a multifactorial disease influenced by both genetic and environmental risk factors. Progression of AMD is characterized by an increase in the number and size of drusen, extracellular deposits, which accumulate between the retinal pigment epithelium (RPE) and Bruch’s membrane (BM) in outer retina. The major pathways associated with its pathogenesis include oxidative stress and inflammation in the early stages of AMD. Little is known about the interactions among these mechanisms that drive the transition from early to late stages of AMD, such as geographic atrophy (GA) or choroidal neovascularization (CNV). As part of the innate immune system, inflammasome activation has been identified in RPE cells and proposed to be a causal factor for RPE dysfunction and degeneration. Here, we will first review the classic model of inflammasome activation, then discuss the potentials of AMD‐related factors to activate the inflammasome in both nonocular immune cells and RPE cells, and finally introduce several novel mechanisms for regulating the inflammasome activity.
La Doping of CdS for Enhanced CdS/CdSe Quantum Dot Cosensitized Solar Cells
Authors: Qi Xiaolei , Zou Xiaoping , He Sheng
Published: January 2015

CdS/CdSe system of quantum dot cosensitized solar cells (QDCSCs) is one of the most attractive structures for high-efficiency due to its effect of level adjusting. However, the stepwise structure formed between levels of CdS and CdSe has a limitation for enhancing the efficiencies. Metal ions doping in quantum dots have emerged as a common way for changing the Fermi level, band gap, and conductance. Here we report an innovative concept for the rare earth materials La-doped of the CdS layer in the CdS/CdSe QDCSCs by means of the successive ionic layer adsorption and reaction (SILAR). Then we tested that La doped quantum dots can help more electrons accumulate in CdS film, which makes the Fermi level shift up and form a stepped structure. This method leads to enhanced absorption intensity, obviously increasing current density in CdS/CdSe QDCSCs. Our research is a new exploration for improving efficiencies of quantum dot sensitized solar cells.
Long Complete Remission Achieved with the Combination Therapy of Cisplatin and Gemcitabine in a Patient with Aggressive Natural Killer Cell Leukemia
Authors: LaPorte Justin , Morris Lawrence , Koepke John
Published: January 2015

Aggressive natural killer cell leukemia (ANKL) is a rare and often lethal lymphoproliferative disorder. Patients may present with constitutional symptoms, jaundice, skin infiltration, lymphadenopathy, and hepatosplenomegaly. ANKL can progress quickly to multiorgan failure and survival is usually measured in weeks. Although a rapid and accurate diagnosis is critical, unfortunately there is no hallmark diagnostic marker of ANKL. We report a case of a 48-year-old male who was able to obtain a complete remission following cisplatin-based chemotherapy. We describe the details of the chemotherapy regimens used and a literature review of the treatment of ANKL.
Synthesis of Micro- and Nanoparticles of Metal Oxides and Their Application for Reinforcement of Al-Based Alloys
Authors: Vorozhtsov S. , Zhukov I. , Vorozhtsov A. , Zhukov A. , Eskin D. , Kvetinskaya A.
Published: January 2015

This paper presents a comparative analysis of morphology, chemical and phase compositions, and particle size distribution of nanopowders produced by electric explosion of wire (EEW) and plasma-chemical methods. The possibility of introduction of Al2O3particles into Al alloy by means of a special master alloy and with ultrasonic processing is shown. The improvement of tensile properties of an Al-based composite material reinforced with 0.1 wt% of EEW Al2O3is demonstrated.
High Sensitive Sensor Fabricated by Reduced Graphene Oxide/Polyvinyl Butyral Nanofibers for Detecting Cu (II) in Water
Authors: Ding Rui , Luo Zhimin , Ma Xiuling , Fan Xiaoping , Xue Liqun , Lin Xiuzhu , Chen Sheng
Published: January 2015

Graphene oxide (GO)/polyvinyl butyral (PVB) nanofibers were prepared by a simple electrospinning technique with PVB as matrix and GO as a functional nanomaterial. GO/PVB nanofibers on glassy carbon electrode (GCE) were reduced through electrochemical method to form reduced graphene oxide (RGO)/PVB nanofibers. The morphology and structure of GO/PVB nanofiber were studied by scanning election microscopy (SEM), transmission electron microscopy (TEM), and Fourier transform infrared (FTIR). RGO/PVB modified GCE was used for fabricating an electrochemical sensor for detecting Cu (II) in water. The analysis results showed that RGO/PVB modified GCE had good analytical results with the linear range of 0.06–2.2 μM, detection limit of 4.10 nM (S/N=3), and the sensitivity of 103.51 μA·μM−1·cm−2.
A Case of Typhoid Fever with Hepatic Granulomas and Enteritis
Authors: Narechania Shraddha , Duran Marc , Karivedu Vidhya , Gopalakrishna K. V.
Published: January 2015

The common histopathologic hepatic manifestations in patients infected withSalmonellainclude cloudy swelling and balloon degeneration with vacuolation of the hepatocytes and steatosis. Hepatic granulomas are a very rare finding, so far reported in very few cases. We report a 64-year-old patient withSalmonellaenteritis who was found to have multiple 1.4 to 1.6 cm hypoechoic liver masses on ultrasound of the abdomen which on biopsy revealed hepatic granulomas. This case highlights the importance of keeping the differential diagnosis ofSalmonella typhi(S. typhi) in mind in a patient with hepatic granulomas.
Robust Adaptive Beamforming Based on Worst-Case and Norm Constraint
Authors: Li Hongtao , Wang Ke , Wang Chaoyu , He Yapeng , Zhu Xiaohua
Published: January 2015

A novel robust adaptive beamforming based on worst-case and norm constraint (RAB-WC-NC) is presented. The proposed beamforming possesses superior robustness against array steering vector (ASV) error with finite snapshots by using the norm constraint and worst-case performance optimization (WCPO) techniques. Simulation results demonstrate the validity and superiority of the proposed algorithm.
Separation of the Proximal Humeral Epiphysis in the Newborn: Rapid Diagnosis with Ultrasonography
Authors: Goldfisher Rachelle , Amodio John
Published: January 2015

Separation of the proximal humeral epiphysis (SPHE) is a well-known occurrence and may occur secondary to trauma, infection, and nonaccidental trauma. Since most newborns do not have the proximal humeral epiphysis ossified at birth, the diagnosis may be difficult to make on routine radiographs. Ultrasonography of the shoulder in the newborn is rapid, noninvasive, and nonionizing imaging techniques which can diagnose SPHE. In this report, we describe and emphasize the diagnostic utility of state-of-the-art ultrasonography for the diagnosis of SPHE.
Blood Vessel Matrix Seeded with Cells: A Better Alternative for Abdominal Wall Reconstruction—A Long-Term Study
Authors: Nowacki Maciej , Jundziłł Arkadiusz , Nazarewski Łukasz , Kotela Andrzej , Kloskowski Tomasz , Skopińska-Wisniewska Joanna , Bodnar Magdalena , Łukasiewicz Aleksander , Nazarewski Sławomir , Kotela Ireneusz , Kucharzewski Marek , Pokrywczyńska Marta , Marszałek Andrzej , Drewa Tomasz
Published: January 2015

Purpose. The aim of this study was to present abdominal wall reconstruction using a porcine vascular graft seeded with MSC (mesenchymal stem cells) on rat model.Material and Methods. Abdominal wall defect was prepared in 21 Wistar rats. Acellular porcine-vascular grafts taken from aorta and prepared with Triton X were used. 14 aortic grafts were implanted in place, of which 7 grafts were seeded with rat MSC cells (Group I), and 7 were acellular grafts (Group II). As a control, 7 standard polypropylene meshes were used for defect augmentation (Group III). The assessment method was performed by HE and CD31 staining after 6 months. The mechanical properties have been investigated by Zwick&Roell Z0.5.Results. The strongest angiogenesis and lowest inflammatory response were observed in Group I. Average capillaries density was 2.75, 0.75, and 1.53 and inflammatory effect was 0.29, 1.39, and 2.72 for Groups I, II, and III, respectively. The means of mechanical properties were12.74±1.48,7.27±1.56, and14.4±3.7 N/cm in Groups I and II and control, respectively.Conclusions. Cell-seeded grafts have better mechanical properties than acellular grafts but worse than polypropylene mesh. Cells improved mechanical and physiological properties of decellularized natural scaffolds.
Large-Vessel Vasculitis: Interobserver Agreement and Diagnostic Accuracy of18F-FDG-PET/CT
Authors: Lensen K. D. F. , Comans E. F. I. , Voskuyl A. E. , van der Laken C. J. , Brouwer E. , Zwijnenburg A. T. , Pereira Arias-Bouda L. M. , Glaudemans A. W. J. M. , Slart R. H. J. A. , Smulders Y. M.
Published: January 2015

Introduction.18F-FDG-PET visualises inflammation. Both atherosclerosis and giant cell arteritis cause vascular inflammation, but distinguishing the two may be difficult. The goal of this study was to assess interobserver agreement and diagnostic accuracy of18F-FDG-PET for the detection of large artery involvement in giant cell arteritis (GCA).Methods. 3118F-FDG-PET/CT scans were selected from 2 databases. Four observers assessed vascular wall18F-FDG uptake, initially without and subsequently with predefined observer criteria (i.e., vascular wall18F-FDG uptake compared to liver or femoral artery18F-FDG uptake). External validation was performed by two additional observers. Sensitivity and specificity of18F-FDG-PET were determined by comparing scan results to a consensus diagnosis.Results. The highest interobserver agreement (kappa: 0.96 in initial study and 0.79 in external validation) was observed when vascular wall18F-FDG uptake higher than liver uptake was used as a diagnostic criterion, although agreement was also good without predefined criteria (kappa: 0.68 and 0.85). Sensitivity and specificity were comparable for these methods. The criterion of vascular wall18F-FDG uptake equal to liver18F-FDG uptake had low specificity.Conclusion. Standardization of image assessment for vascular wall18F-FDG uptake promotes observer agreement, enables comparative studies, and does not appear to result in loss of diagnostic accuracy compared to nonstandardized assessment.
The PI3K/Akt Signaling Pathway Mediates the High Glucose-Induced Expression of Extracellular Matrix Molecules in Human Retinal Pigment Epithelial Cells
Authors: Qin Dong , Zhang Guo-ming , Xu Xun , Wang Li-ya
Published: January 2015

Prolonged hyperglycemia is an important risk factor of the pathogenesis of diabetic retinopathy (DR). Extracellular matrix molecules, such as fibronectin, collagen IV, and laminin, are associated with fibrotic membranes. In this study, we investigated the expression of fibronectin, collagen IV, and laminin in RPE cells under high glucose conditions. Furthermore, we also detected the phosphorylation of protein kinase B (Akt) under high glucose conditions in RPE cells. Our results showed that high glucose upregulated fibronectin, collagen IV, and laminin expression, and activated Akt in RPE cells. We also found that pretreatment with LY294002 (an inhibitor of phosphatidylinositol 3-kinase) abolished high glucose-induced expression of fibronectin, collagen IV, and laminin in RPE cells. Thus, high glucose induced the expression of fibronectin, collagen IV, and laminin through PI3K/Akt signaling pathway in RPE cells, and the PI3K/Akt signaling pathway may contribute to the formation of fibrotic membrane during the development of DR.
A General Class of Derivative Free Optimal Root Finding Methods Based on Rational Interpolation
Authors: Zafar Fiza , Yasmin Nusrat , Akram Saima , Junjua Moin-ud-Din
Published: January 2015

We construct a new general class of derivative free n‐point iterative methods of optimal order of convergence 2n−1 using rational interpolant. The special cases of this class are obtained. These methods do not need Newton’s iterate in the first step of their iterative schemes. Numerical computations are presented to show that the new methods are efficient and can be seen as better alternates.
Self-Referenced Plasmon Waveguide Resonance Sensor Using Different Waveguide Modes
Authors: Zhang Pengfei , Liu Le , He Yonghong , Ji Yanhong , Ma Hui
Published: January 2015

We report a plasmon waveguide resonance (PWR) sensing structure supporting two waveguide modes for self-referenced measurement. We show theoretically the dual mode PWR sensing structure owns unique opportunities for self-referenced measurement, and the accuracy and cross sensitivity can be optimized by simply varying the gold film thickness or dielectric layer thickness or dielectric film refractive index. This structure may provide an approach owning good compatibility with the surface plasmon resonance and PWR biosensors for self-referenced biosensing.
Evolution ofM. bovisBCG Vaccine: Is Niacin Production Still a Valid Biomarker?
Authors: Singh Sarman , Kumar Manoj , Singh Pragati
Published: January 2015

BCG vaccine is usually considered to be safe though rarely serious complications have also been reported, often incriminating contamination of the seed strain with pathogenicMycobacterium tuberculosis. In such circumstances, it becomes prudent to rule out the contamination of the vaccine seed.M. bovisBCG can be confirmed by the absence of nitrate reductase, negative niacin test, and resistance to pyrazinamide and cycloserine. Recently in India, some stocks were found to be niacin positive which led to a national controversy and closer of a vaccine production plant. This prompted us to write this review and the comparative biochemical and genotypic studies were carried out on the these contentious vaccine stocks at the Indian vaccine plant and other seeds and it was found that some BCG vaccine strains and even some strains ofM. boviswith eugenic-growth characteristics mainly old laboratory strains may give a positive niacin reaction. Most probably, the repeated subcultures lead to undefined changes at the genetic level in these seed strains. These changing biological characteristics envisage reevaluation of biochemical characters of existing BCG vaccine seeds and framing of newer guidelines for manufacturing, production, safety, and effectiveness of BCG vaccine.
Valsalva-Like Retinopathy Secondary to Pancytopenia following Induction of Etoposide and Ifosfamide
Authors: Prinzi Robert A. , Saraf Steven , Desai Ankit , Kuruvilla Oscar , Desai Uday R.
Published: January 2015

Etoposide and ifosfamide are chemotherapeutic agents used frequently in the treatment of sarcomas and hematologic malignancies. Ocular side effects are rarely reported. We describe a case of a patient on etoposide and ifosfamide who presented with unilateral vision loss, anemia, and thrombocytopenia. The patient was found to have a large subinternal limiting membrane hemorrhage in the right eye that is thought to be related to his anemia and thrombocytopenia. The hemorrhage resolved spontaneously after 10 days. This case illustrates how bone marrow suppression by chemotherapeutic agents may indirectly contribute to retinal hemorrhages resulting in at least transient vision loss.
Treatment of Invasive Brain Tumors Using a Chain-like Nanoparticle
Authors: Peiris Pubudu M. , Abramowski Aaron , Mcginnity James , Doolittle Elizabeth , Toy Randall , Gopalakrishnan Ramamurthy , Shah Shruti , Bauer Lisa , Ghaghada Ketan B. , Hoimes Christopher , Brady-Kalnay Susann M. , Basilion James P. , Griswold Mark A. , Karathanasis Efstathios
Published: January 2015

Glioblastoma multiforme is generally recalcitrant to current surgical and local radiotherapeutic approaches. Moreover, systemic chemotherapeutic approaches are impeded by the blood–tumor barrier. To circumvent limitations in the latter area, we developed a multicomponent, chain-like nanoparticle that can penetrate brain tumors, composed of three iron oxide nanospheres and one drug-loaded liposome linked chemically into a linear chain-like assembly. Unlike traditional small-molecule drugs or spherical nanotherapeutics, this oblong-shaped, flexible nanochain particle possessed a unique ability to gain access to and accumulate at glioma sites. Vascular targeting of nanochains to the αvβ3 integrin receptor resulted in a 18.6-fold greater drug dose administered to brain tumors than standard chemotherapy. By 2 hours after injection, when nanochains had exited the blood stream and docked at vascular beds in the brain, the application of an external low-power radiofrequency field was sufficient to remotely trigger rapid drug release. This effect was produced by mechanically induced defects in the liposomal membrane caused by the oscillation of the iron oxide portion of the nanochain. In vivo efficacy studies conducted in two different mouse orthotopic models of glioblastoma illustrated how enhanced targeting by the nanochain facilitates widespread site-specific drug delivery. Our findings offer preclinical proof-of-concept for a broadly improved method for glioblastoma treatment. Cancer Res; 75(7); 1356–65. ©2015 AACR.
Emergence of Drug Tolerance in Cancer Cell Populations: An Evolutionary Outcome of Selection, Nongenetic Instability, and Stress-Induced Adaptation
Authors: Chisholm Rebecca H. , Lorenzi Tommaso , Lorz Alexander , Larsen Annette K. , Almeida Luís Neves de , Escargueil Alexandre , Clairambault Jean
Published: January 2015

In recent experiments on isogenetic cancer cell lines, it was observed that exposure to high doses of anticancer drugs can induce the emergence of a subpopulation of weakly proliferative and drug-tolerant cells, which display markers associated with stem cell–like cancer cells. After a period of time, some of the surviving cells were observed to change their phenotype to resume normal proliferation and eventually repopulate the sample. Furthermore, the drug-tolerant cells could be drug resensitized following drug washout. Here, we propose a theoretical mechanism for the transient emergence of such drug tolerance. In this framework, we formulate an individual-based model and an integro-differential equation model of reversible phenotypic evolution in a cell population exposed to cytotoxic drugs. The outcomes of both models suggest that nongenetic instability, stress-induced adaptation, selection, and the interplay between these mechanisms can push an actively proliferating cell population to transition into a weakly proliferative and drug-tolerant state. Hence, the cell population experiences much less stress in the presence of the drugs and, in the long run, reacquires a proliferative phenotype, due to phenotypic fluctuations and selection pressure. These mechanisms can also reverse epigenetic drug tolerance following drug washout. Our study highlights how the transient appearance of the weakly proliferative and drug-tolerant cells is related to the use of high-dose therapy. Furthermore, we show how stem-like characteristics can act to stabilize the transient, weakly proliferative, and drug-tolerant subpopulation for a longer time window. Finally, using our models as in silico laboratories, we propose new testable hypotheses that could help uncover general principles underlying the emergence of cancer drug tolerance. Cancer Res; 75(6); 930–9. ©2015 AACR.
Plumbagin Inhibits Prostate Carcinogenesis in Intact and Castrated PTEN Knockout Mice via Targeting PKCϵ, Stat3, and Epithelial-to-Mesenchymal Transition Markers
Authors: Hafeez Bilal Bin , Fischer Joseph W. , Singh Ashok , Zhong Weixiong , Mustafa Ala , Meske Louise , Sheikhani Mohammad Ozair , Verma Ajit Kumar
Published: January 2015

Prostate cancer continues to remain the most common cancer and the second leading cause of cancer-related deaths in American males. The Pten deletions and/or mutations are frequently observed in both primary prostate cancers and metastatic prostate tissue samples. Pten deletion in prostate epithelium in mice results in prostatic intraepithelial neoplasia (PIN), followed by progression to invasive adenocarcinoma. The Pten conditional knockout mice [(Pten-loxp/loxp:PB-Cre4+) (Pten-KO)] provide a unique preclinical model to evaluate agents for efficacy for both the prevention and treatment of prostate cancer. We present here for the first time that dietary plumbagin, a medicinal plant–derived naphthoquinone (200 or 500 ppm) inhibits tumor development in intact as well as castrated Pten-KO mice. Plumbagin has shown no signs of toxicity at either of these doses. Plumbagin treatment resulted in a decrease expression of PKCϵ, AKT, Stat3, and COX2 compared with the control mice. Plumbagin treatment also inhibited the expression of vimentin and slug, the markers of epithelial-to-mesenchymal transition (EMT) in prostate tumors. In summary, the results indicate that dietary plumbagin inhibits growth of both primary and castration-resistant prostate cancer (CRPC) in Pten-KO mice, possibly via inhibition of PKCϵ, Stat3, AKT, and EMT markers (vimentin and slug), which are linked to the induction and progression of prostate cancer. Cancer Prev Res; 8(5); 375–86. ©2015 AACR.
Three Steps to Breaking Immune Tolerance to Lymphoma: A Microparticle Approach
Authors: Makkouk Amani , Joshi Vijaya B. , Lemke Caitlin D. , Wongrakpanich Amaraporn , Olivier Alicia K. , Blackwell Sue E. , Salem Aliasger K. , Weiner George J.
Published: January 2015

In situ immunization aims at generating antitumor immune responses through manipulating the tumor microenvironment. On the basis of recent advances in the understanding of antitumor immunity, we designed a three-step approach to in situ immunization to lymphoma: (i) inducing immunogenic tumor cell death with the chemotherapeutic drug doxorubicin. Doxorubicin enhances the expression of “eat-me” signals by dying tumor cells, facilitating their phagocytosis by dendritic cells (DC). Because of the vesicant activity of doxorubicin, microparticles made of biodegradable polymer poly(lactide-co-glycolide) or PLGA can safely deliver doxorubicin intratumorally and are effective vaccine adjuvants, (ii) enhancing T-cell activation using anti-OX40 and (iii) sustaining T-cell responses by checkpoint blockade using anti–CTLA-4. In vitro, doxorubicin microparticles were less cytotoxic to DCs than to B lymphoma cells, did not require internalization by tumor cells, and significantly enhanced phagocytosis of tumor cells by DCs as compared with soluble doxorubicin. In mice, this three-step therapy induced CD4- and CD8-dependent systemic immune responses that enhanced T-cell infiltration into distant tumors, leading to their eradication and significantly improving survival. Our findings demonstrate that systemic antitumor immune responses can be generated locally by three-step therapy and merit further investigation as an immunotherapy for patients with lymphoma. Cancer Immunol Res; 3(4); 389–98. ©2015 AACR.
Chronic Kidney Disease and the Ageing Population
Authors: Tonelli Marcello , Riella Miguel
Published: January 2015

Due to improvements in socioeconomic development and increased life expectancy, the proportion of older people in the general population is increasing worldwide. While this trend is something to celebrate, it also brings with it challenges for health care systems. One particular challenge is an increase in chronic kidney disease, the prevalence of which is higher in older people. This article reviews the key links between kidney function, age, health and illness, and discusses the implications of the ageing population for the care of people with chronic kidney disease.
Characterization of the Arginolytic Microflora Provides Insights into pH Homeostasis in Human Oral Biofilms
Authors: Huang Xuelian , Schulte Renee M. , Burne Robert A. , Nascimento Marcelle M.
Published: January 2015

A selected group of oral bacteria commonly associated with dental health is capable of producing alkali via the arginine deiminase system (ADS), which has a profound impact on the pH of human oral biofilms. An increased risk for dental caries has been associated with reduced ADS activity of the bacteria in oral biofilms. Arginolytic bacterial strains from dental plaque samples of caries-free and caries-active adults were isolated and characterized to investigate the basis for differences in plaque ADS activity between individuals. Fifty-six ADS-positive bacterial strains were identified by 16S rRNA gene sequencing, and their ADS activity levels were compared under standard growth conditions. The spectrum of bacterial ADS activity ranged from 45.2 to 688.0 units (mg protein)-1. Although Streptococcus sanguinis was the most prevalent species, other Streptococcus sp. were also represented. Biochemical assays carried out using 27 ADS-positive strains under conditions known to induce or repress ADS gene expression showed substantial variation in arginolytic activity in response to pH, oxygen and the availability of carbohydrate or arginine. This study reveals that the basis for the wide spectrum of arginolytic expression observed among clinical strains is, at least in part, attributable to differences in the regulation of the ADS within and between species. The results provide insights into the microbiological basis for intersubject differences in ADS activity in oral biofilms and enhance our understanding of dental caries as an ecologically driven disease in which arginine metabolism moderates plaque pH and promotes dental health.
Brachial Artery Flow Mediated Dilation in the First Trimester to Predict the Occurrence of Hypertensive Disorders during Pregnancy
Authors: Alves Júlio A.G. , Miyague Andre H. , de Sousa Paulo C.P. , Maia Sammya B. , da Silva Costa Fabricio , Martins Wellington P.
Published: January 2015

Objectives: To determine whether brachial artery flow-mediated dilation (FMD) assessed by ultrasonography during the late first trimester is able to predict the occurrence of hypertensive disorders during pregnancy. Methods: Maternal endothelial function was assessed by flow-mediated dilation (FMD) of the brachial artery in 487 pregnant women at 11-13+6 weeks' gestation. Subjects were prospectively followed and grouped according to the outcomes related to hypertensive disorders. We determined the areas under receiver operating characteristic (ROC) curve with their respective 95% confidence intervals (CI) for using low FMD results to predict the occurrence of hypertensive disorders during pregnancy. Results: Among 487 women, 9 (1.8%) were diagnosed with early-onset preeclampsia, 22 (4.5%) were diagnosed with late-onset preeclampsia, 47 (9.7%) developed gestational hypertension, and the remaining 409 (84%) pregnancies were unaffected by hypertensive disorders. Area under ROC curve analyses demonstrated that FMD was not able to predict pregnancies that developed hypertensive disorders. Conclusions: We conclude that FMD should not be considered a potential first-trimester marker of hypertensive disorders during pregnancy.
Ectopic Expression of Fatty Acid-Binding Protein 4 in the Glomerulus Is Associated with Proteinuria and Renal Dysfunction
Authors: Tanaka Marenao , Furuhashi Masato , Okazaki Yusuke , Mita Tomohiro , Fuseya Takahiro , Ohno Kohei , Ishimura Shutaro , Yoshida Hideaki , Miura Tetsuji
Published: January 2015

Background/Aims: Fatty acid-binding proteins (FABPs) are a family of intracellular lipid chaperones. Among FABPs, FABP1 (liver FABP) is expressed in proximal tubular epithelial cells in the kidney, and urinary FABP1 has been reported to reflect damage of proximal tubular epithelial cells. However, roles of other FABP isoforms in renal pathologies have not been reported. Recently, FABP4 (adipocyte FABP/aP2) was reported to be expressed in peritubular capillaries (PTCs), but not in glomerular capillaries in the normal kidney. We examined the hypothesis that pathological conditions alter the level and localization of FABP4 expression in the kidney, which mediates renal dysfunction. Methods: A total of 112 consecutive patients who underwent renal biopsy were retrospectively enrolled. Expression of FABP4 protein and mRNA in the kidney was examined by immunohistochemistry and in situ hybridization, respectively. The ratio of FABP4-positive area to total area within glomeruli (G-FABP4-Area), urinary protein level (U-Protein), and change in estimated glomerular filtration rate (eGFR) 1 year after biopsy were examined. Results: FABP4 protein and mRNA were expressed not only in PTCs, but also in endothelial cells and macrophages in the glomerulus. G-FABP4-Area was correlated with U-Protein (r = 0.497, p < 0.001). As a subanalysis, in patients with IgA nephropathy (n = 34), G-FABP4-Area was significantly larger in cases with an endocapillary proliferative lesion, and change in eGFR was negatively correlated with G-FABP4-Area at baseline (r = -0.537, p = 0.008). Conclusion: Ectopic FABP4 expression in the glomerulus is induced by renal diseases and is closely associated with proteinuria and renal dysfunction.
Sex-Dependent Association between Heart Rate Variability and Pulse Pressure in Haemodialysis Patients
Authors: Poulikakos Dimitrios , Malik Marek , Banerjee Debasish
Published: January 2015

Aims: Increased pulse pressure (PP) is associated with increased cardiovascular mortality in haemodialysis (HD) patients. Autonomic imbalance is common in HD patients and predisposes to sudden cardiac death, but its relationship to PP is unknown. We investigated the relationship between cardiac autonomic modulation assessed by heart rate variability (HRV) and PP in HD patients. Methods: Continuous electrocardiograms recorded during HD sessions were repeated 5 times at 2-week intervals in stable HD patients. The high-frequency (HF) and low-frequency (LF) components and the LF/HF ratio of HRV were calculated during the first and last hour of the recordings. These values and the corresponding systolic blood pressure (SBP), diastolic blood pressure (DBP) and PP measurements were averaged in repeated recordings of each patient. Results: Seventy-six patients were included in the final analysis (aged 61 ± 15 years, 32% females, 37% diabetics). In male patients, LF/HF correlated inversely with pre- and post-HD PP (r = -0.369, p = 0.007 and r = -0.546, p = 0.000, respectively), positively with pre- and post-HD DBP (r = 0.358, p = 0.009 and r = 0.306, p = 0.028, respectively) and inversely with post-HD SBP (r = -0.350, p = 0.011). In female patients, LF/HF correlated positively with post-HD SBP (r = 0.422, p = 0.040). Conclusion: We observed an association between PP and HRV in male HD patients. Sex differences may be important for cardiac risk assessment.
Biologic Therapy in Lupus Nephritis
Authors: Houssiau Frédéric A.
Published: January 2015

This position paper critically analyzes the available controlled data regarding biologic therapy in lupus nephritis (LN). Rather than an exhaustive review of all published evidence, the stress is put on the unmet medical needs in LN, the design of trials aimed at testing the effect of a biologic in LN, the possible reasons for LN trial failures and the future of biological therapy in LN.
Anti-Phospholipase A2 Receptor Antibodies and the Pathogenesis of Membranous Nephropathy
Authors: Ronco Pierre , Debiec Hanna
Published: January 2015

Since the early 2000s, considerable advances have been achieved in the understanding of molecular pathomechanisms of human membranous nephropathy (MN), inspired by studies of Heymann nephritis, a faithful experimental model. These studies led to the identification of neutral endopeptidase, the type-M phospholipase A2 receptor (PLA2R), and cationic bovine serum albumin as target antigens of circulating and deposited antibodies in neonatal alloimmune, adult ‘idiopathic', and early childhood MN, respectively. A genome-wide association study further showed a highly significant association of the PLA2R1 and the HLA-DQA1 loci with idiopathic MN in patients of white ancestry. The time has come to revisit the spectrum of MN based on the newly identified antigen-antibody systems which should be considered as molecular signatures of the disease, challenging the uniform histological definition. Although some uncertainties remain as to the pathogenic effects of anti-PLA2R antibodies because of the lack of an appropriate experimental model, the value of these antibodies as biomarkers for diagnosis and disease activity is increasingly being recognized. It is not exaggerated to state that they have induced a paradigm shift in the monitoring of patients with MN, thus opening a new era of personalized medicine.
Rituximab in Primary Membranous Nephropathy: First-Line Therapy, Why Not?
Authors: Cravedi Paolo , Remuzzi Giuseppe , Ruggenenti Piero
Published: January 2015

The ideal treatment of patients with primary membranous nephropathy (MN) and persistent nephrotic syndrome (NS) is still a matter of debate. This is a major issue since these patients may progress to end-stage kidney disease (ESKD) in 5-10 years. Steroids, alkylating agents, and calcineurin inhibitors have been suggested to achieve NS remission and prevent ESKD in this population. Treatment benefits, however, are uncertain and are often offset by serious adverse events (SAEs). Evidence that B cells play a crucial role in the pathogenesis of the disease, both as precursors of autoantibody-producing cells and as antigen-presenting cells, provided the background for explorative studies testing the role of B cell-depletion therapy with the monoclonal antibody rituximab. This approach aimed at selectively inhibiting disease mechanisms without the devastating consequences of unspecific immunosuppression. Finding that rituximab safely ameliorated NS in 8 patients with primary MN fueled a series of observational studies that uniformly confirmed the safety/efficacy profile of rituximab in this context. Although head-to-head comparisons in randomized clinical trials are missing, comparative analyses between series of homogeneous patient cohorts clearly show at least similar efficacy of rituximab as compared to steroid plus alkylating agents. Moreover, data confirm the dramatically superior safety profile of rituximab that actually appears to be associated with a rate of SAEs even lower than that observed with conservative therapy. Rituximab is also effective in patients resistant to other treatments and its cost-effectiveness is further increased when treatment is titrated to circulating B cells. Recently identified pathogenic antibodies against the M type phospholipase A2 receptor will likely provide a novel tool to monitor disease activity and drive rituximab therapy, at least in a subset of patients. Newly developed anti-CD20 antibodies could represent a valuable option for those who fail rituximab therapy. Steroids, alkylating agents, and calcineurin inhibitors should likely be abandoned.
Complement and Glomerular Diseases
Authors: Popat Reena J. , Robson Michael G.
Published: January 2015

The complement pathway is a central part of the innate immune system and also modulates adaptive immunity. It is implicated in the pathogenesis of glomerular disease by a number of clinical findings. These include the presence of complement components in renal biopsy samples, decreases in circulating levels indicating consumption, the presence of autoantibodies to complement proteins and the association of genetic mutations with disease either in individuals or within families. Further support and mechanistic insights comes from animal models. This review provides an overview of the role of complement in glomerular diseases and discusses the data from patients and animal models with reference to specific diseases. These include atypical haemolytic uraemic syndrome, C3 glomerulopathy, anti-neutrophil cytoplasmic antibody vasculitis, lupus nephritis and membranous nephropathy. The implications for therapy are also discussed.
Neue Inhalationshilfen - Die guten und die schlechten Nachrichten
Authors: Lavorini Federico , Fontana Giovanni A. , Usmani Omar S.
Published: January 2015

Aerosole sind eine wirkungsvolle Art, Arzneimittel gezielt in die Lunge einzubringen, um obstruktive Atemwegserkrankungen wie Asthma und chronisch-obstruktive Lungenerkrankung (COPD) zu behandeln. In den letzten 10 Jahren sind mehrere neue Arzneimittel zur Behandlung von Asthma und COPD auf den Markt gekommen; weitere befinden sich in der Entwicklung. Begleitend zu diesen neuen Wirkstoffen für Atemwegserkrankungen sind bei allen Arten von Systemen für deren pulmonale Verabreichung Fortschritte erzielt worden, die die Performance bei der Aerosolerzeugung, die konsistente Wirksamkeit und die Adhärenz verbessern sollen. Im Folgenden geben wir einen Überblick über die technischen Fortschritte und Innovationen bei aktuellen Inhalationsgeräten und die sich verändernden Rollen von Druckgas-Dosierinhalatoren, Pulverinhalatoren und Verneblern sowie deren Bedeutung für die Therapietreue der Patienten.
Inhalation von Antibiotika bei nicht durch Mukoviszidose bedingter Bronchiektasie
Authors: Rubin Bruce K. , Williams Ronald W.
Published: January 2015

Die nicht durch Mukoviszidose bedingte Bronchiektasie (non-cystic fibrosis bronchiectasis; NCFB) ähnelt in vielen respiratorischen Merkmalen und in der Krankheitsprogression der Mukoviszidose (cystic fibrosis; CF). Da es keine zugelassenen Therapien für das Management der NCFB gibt, besteht ein gängiger Behandlungsansatz darin, ähnlich wie bei der CF vorzugehen. In vielen Fällen erweist sich ein solches Vorgehen jedoch als unwirksam oder sogar schädlich. Der Grund hierfür ist nicht bekannt, er könnte jedoch in zentralen Unterschieden in der Pathogenese liegen. Die Fragen, die sich hieraus ergeben, haben Anlass zu reger Forschungstätigkeit im Hinblick auf ein NCFB-spezifisches therapeutisches Vorgehen gegeben. Patienten mit NCFB haben chronische bakterielle Infektionen; die Bakterienlast korreliert mit der Symptomatik und Lebensqualität. Eine Behandlung mit systemischen Antibiotika reduziert die Bakterienlast und kann sich günstig auf weitere Parameter auswirken. Die chronische oder häufige Anwendung systemischer Antibiotika ist jedoch nicht praktikabel und nicht immer sicher, darum gelten Aerosole als attraktive alternative Verabreichungsform. Das klinische Ansprechen auf inhalative Antibiotika und die Verträglichkeit einer solchen Therapie unterscheiden sich bei NCFB und CF signifikant. Neue Inhalatortechnologien, neuartige Antibiotikaformulierungen und fortgeschrittene Erkenntnisse über die Bakterienlast bei NCFB sind im Begriff, das Management dieser Krankheit von Grund auf zu verändern.