bluuebunny/crossref_metadata_2025 huggingface dataset:
Nontypeable Pneumococci Can Be Divided into Multiple
cps
Types, Including One Type Expressing the Novel Gene
pspK
Authors: Park In Ho , Kim Kyung-Hyo , Andrade Ana Lucia , Briles David E. , McDaniel Larry S. , Nahm Moon H.
Published: April 2012

Although virulence of
Streptococcus pneumoniae
is associated with its capsule, some pathogenic
S. pneumoniae
isolates lack capsules and are serologically nontypeable (NT). We obtained 64 isolates that were identified as NT “pneumococci” (i.e., bacteria satisfying the conventional definition but without the multilocus sequence typing [MLST]-based definition of
S. pneumoniae
) by the traditional criteria. All 64 were optochin sensitive and had
lytA
, and 63 had
ply
. Twelve isolates had
cpsA
, suggesting the presence of a conventional but defective capsular polysaccharide synthesis (
cps
) locus. The 52
cpsA-
negative isolates could be divided into three null capsule clades (NCC) based on
aliC
(
aliB-
like ORF1),
aliD
(
aliB-
like ORF2), and our newly discovered gene,
pspK
, in their
cps
loci.
pspK
encodes a protein with a long alpha-helical region containing an LPxTG motif and a YPT motif known to bind human pIgR. There were nine isolates in NCC1 (
pspK
+
but negative for
aliC
and
aliD
), 32 isolates in NCC2 (
aliC
+
aliD
+
but negative for
pspK
), and 11 in NCC3 (
aliD
+
but negative for
aliC
and
pspK
). Among 52
cpsA-
negative isolates, 41 were identified as
S. pneumoniae
by MLST analysis. All NCC1 and most NCC2 isolates were
S. pneumoniae
, whereas all nine NCC3 and two NCC2 isolates were not
S. pneumoniae
. Several NCC1 and NCC2 isolates from multiple individuals had identical MLST and
cps
regions, showing that unencapsulated
S. pneumoniae
can be infectious among humans. Furthermore, NCC1 and NCC2
S. pneumoniae
isolates could colonize mice as well as encapsulated
S. pneumoniae
, although
S. pneumoniae
with an artificially disrupted
cps
locus did not. Moreover, an NCC1 isolate with
pspK
deletion did not colonize mice, suggesting that
pspK
is critical for colonization. Thus, PspK may provide pneumococci a means of surviving in the nasopharynx without capsule.

IMPORTANCE
The presence of a capsule is critical for many pathogenic bacteria, including pneumococci. Reflecting the pathogenic importance of the pneumococcal capsule, pneumococcal vaccines are designed to elicit anticapsule antibodies. Additional evidence for the pathogenic importance of the pneumococcal capsule is the fact that in pneumococci all the genes necessary for capsule production are together in one genetic locus, which is called the
cps
locus. However, there are occasional pathogenic pneumococci without capsules, and how they survive in the host without the capsule is unknown. Here, we show that in these acapsular pneumococci, the
cps
loci have been replaced with various novel genes and they can colonize mouse nasopharynges as well as capsulated pneumococci. Since the genes that replace the
cps
loci are likely to be important in host survival, they may show new and/or alternative capsule-independent survival mechanisms used by pneumococci.
HARMONIC MAPS FROM SMOOTH METRIC MEASURE SPACES
Authors: WANG GUOFANG , XU DELIANG
Published: April 2012

In this paper, we study a generalized harmonic map, ϕ-harmonic map, from a smooth metric measure space (M, g, e-ϕ dv) into a Riemannian manifold. We proved various rigidity results for the ϕ-harmonic maps under conditions in terms of the Bakry–Émery Ricci tensor.
A PROPER NONLOCAL FORMULATION OF QUANTUM MAXIMUM ENTROPY PRINCIPLE IN STATISTICAL MECHANICS
Authors: TROVATO M. , REGGIANI L.
Published: April 2012

By considering Wigner formalism, the quantum maximum entropy principle (QMEP) is here asserted as the fundamental principle of quantum statistical mechanics when it becomes necessary to treat systems in partially specified quantum states. From one hand, the main difficulty in QMEP is to define an appropriate quantum entropy that explicitly incorporates quantum statistics. From another hand, the availability of rigorous quantum hydrodynamic (QHD) models is a demanding issue for a variety of quantum systems. Relevant results of the present approach are: (i) The development of a generalized three-dimensional Wigner equation. (ii) The construction of extended quantum hydrodynamic models evaluated exactly to all orders of the reduced Planck constant ℏ. (iii) The definition of a generalized quantum entropy as global functional of the reduced density matrix. (iv) The formulation of a proper nonlocal QMEP obtained by determining an explicit functional form of the reduced density operator, which requires the consistent introduction of nonlocal quantum Lagrange multipliers. (v) The development of a quantum-closure procedure that includes nonlocal statistical effects in the corresponding quantum hydrodynamic system. (vi) The development of a closure condition for a set of relevant quantum regimes of Fermi and Bose gases both in thermodynamic equilibrium and nonequilibrium conditions.
ELECTRO-OPTIC MICROWAVE-LIGHTWAVE CONVERTERS UTILIZING PATCH ANTENNAS WITH ORTHOGONAL GAPS
Authors: WIJAYANTO YUSUF NUR , MURATA HIROSHI , OKAMURA YASUYUKI
Published: April 2012

We propose a new electro-optic microwave-lightwave converter using two orthogonal optical waveguides and patch antennas embedded with two orthogonal gaps. Wireless microwave signals can be received, separated and converted directly to lightwave signals through optical modulation using the proposed device. This device operates with no external power supply and with low microwave distortion. In addition, it enables us to measure the magnitude, phase and polarization of the wireless signal simultaneously. Experimental demonstrations of the device were presented at the operation frequency of 26 GHz. The device can be applied for electromagnetic compatibility test in the radio-over-fiber link.
OVERLAPPING TE AND TM BAND GAPS IN SQUARE LATTICE PHOTONIC CRYSTAL OF HOLLOW DIELECTRIC RODS
Authors: SURYADHARMA RADIUS N. S. , ISKANDAR ALEXANDER A. , TJIA MAY-ON
Published: April 2012

A numerical study is performed on photonic band gap of 2D square lattice photonic crystal with varied layered dielectric rods by using the plane wave expansion method for the purpose of investigating the effects of geometrical and permittivity variations. The results show that in general the TE and TM band gaps do not coexist in the band structure of this layered rods system. However, for a specific choice of the system parameters leading to a photonic crystals of hollow dielectric rods, both TE and TM photonic band structures feature perceptible band gaps with significant overlap, yielding effective complete photonic band gaps (CPBG). The study further shows that the CPBG can be enlarged by varying both radii of the hollow rods. It is found that a large CPBG can be attained which is comparable in size with those found in hexagonal lattice photonic crystal of air holes as well as square lattice photonic crystal rods incorporating dielectric veins.
GUERRILLA INNOVATION — THE ACCELERATED RADICAL INNOVATION MODEL MEETS THE REAL WORLD
Authors: BERS JOHN A. , DISMUKES JOHN P.
Published: April 2012

The Accelerated Radical Innovation (ARI) methodology, an integrated approach to shepherding radical innovation from initial concept through commercialization, was compared to the approach used by an investor-funded seed-stage innovation incubation firm. Similarities include traversal of the same major stages of innovation, emphasis on front-end analysis before escalating commitments, and using an extended "probe-and-learn" process. Key differences were in emphasis. The ARI model relies on analysis and intelligence gleaned from external sources, while ConduIT views each innovation project as unique, requiring tailored responses that will not be found elsewhere. And while the ARI model relies on a structured process, ConduIT favors a more intuitive, people-centered approach. The message for ARI is to become more flexible and adaptable to each innovation's uniquenesses. For ConduIT the challenges are increasing portfolio turnover and scaling up, which will require a more repeatable, teachable, standardized process such as the ARI model.
Metal insertion into phosphonic acid terminated porphyrins immobilized on TiO2 electrodes
Authors: Erbacher Martin , Viana Ana S. , Abrantes Luísa M. , Montforts Franz-Peter
Published: April 2012

In this study an easy access for modification of properties of porphyrin covered TiO2 electrodes by post-assembling metal insertion was investigated. Therefore a new type of phosphonic acid terminated porphyrin was synthesized and immobilized on mesoporous TiO2 electrodes by self-assembling. Surface concentrations in a range of 1.5–3.3 × 10-8 mol.cm-2, based on the geometric area, were obtained by two independent techniques, UV-vis and cyclic voltammetry. Co(II) , Zn(II) , Pd(II) and Mn(III) ions could be inserted into the immobilized porphyrin by exposing the electrode to a boiling solution of metal chloride in methanol. The electrode surface was characterized by UV-vis spectroscopy and cyclic voltammetry before and after metal insertion. The electrocatalytic activity towards the reduction of molecular oxygen in acidic solution was examined, further confirming metal insertion into immobilized porphyrin monolayer.
THE CHARACTERIZATION, EXPRESSION AND IN SILICO STUDIES ON THE SLC39A13 GENE; IT'S INVOLVEMENT IN BREAST CANCER
Authors: ZAHARI NORMAWATI MOHAMAD , CHONG TEOH TEOW
Published: April 2012

The zinc transporters superfamily is divided into four subfamilies, and SLC39A is one of the subfamilies. The SLC39A subfamily has 9 members. Based on our computer searchers, all 9 sequences each contain 8 transmembranes domains. Since it is related to the zinc transporters superfamily, the SLC39A subfamily may have the same function that is to transport zinc ion. This paper focus on SLC39A13 studies and using the recombinant technology with CHO cells, it is shown that the recombinant protein, pcDNA5/FRT/V5-His-TOPO®-SLC39A13, has 43kD molecular weight. A second study using immunofluorescence technique with MCF-7 cells, it is shown that the recombinant protein expresses intracellularly. Both studies demonstrate that SLC39A13 expresses in breast cancer cells line, therefore the gene has involvement in the development of breast cancer disease. In our computational studies which is divided into two; the homologous study and sequence analysis, both results are supporting our laboratory results. The homologous study using EMBL-EBI and UniProt tools concluded that SLC39A13 is a member to SLC39A subfamily and it is closely related to SLC39A7 member. Although the sequence analysis shows that the molecular weight of SLC39A13 is 38.35kD it is still comparable to our laboratory result. Separately, using Swiss-EMBnet tools, TMpred, has shown that SLC39A13 has 8 transmembranes domains similar to other family members of SLC39A subfamily. Another analysis using EMBL-EBI tools, PPsearch, shows that SLC39A13 has various protein motif such as the protein kinase C phospho, casein kinase II phospho, leucine zipper and ASN-glycosylation sites. These are the useful information that we need when we study its tertiary structure and simulation in the future.
STUDYING THE EFFECT OF ADAPTIVE MOMENTUM IN IMPROVING THE ACCURACY OF GRADIENT DESCENT BACK PROPAGATION ALGORITHM ON CLASSIFICATION PROBLEMS
Authors: REHMAN MUHAMMAD ZUBAIR , NAWI NAZRI MOHD.
Published: April 2012

Despite being widely used in the practical problems around the world, Gradient Descent Back-propagation algorithm comes with problems like slow convergence and convergence to local minima. Previous researchers have suggested certain modifications to improve the convergence in gradient Descent Back-propagation algorithm such as careful selection of input weights and biases, learning rate, momentum, network topology, activation function and value for 'gain' in the activation function. This research proposed an algorithm for improving the working performance of back-propagation algorithm which is 'Gradient Descent with Adaptive Momentum (GDAM)' by keeping the gain value fixed during all network trials. The performance of GDAM is compared with 'Gradient Descent with fixed Momentum (GDM)' and 'Gradient Descent Method with Adaptive Gain (GDM-AG)'. The learning rate is fixed to 0.4 and maximum epochs are set to 3000 while sigmoid activation function is used for the experimentation. The results show that GDAM is a better approach than previous methods with an accuracy ratio of 1.0 for classification problems like Wine Quality, Mushroom and Thyroid disease.
SHORTEST PATH TECHNIQUE FOR SWITCHING IN A MESH NETWORK
Authors: ARIFFIN WAN NOR MUNIRAH , ZIN SHAZALINA MAT , SALLEH SHAHARUDDIN
Published: April 2012

Switching is a technique to route data and instructions between pairs of source-destination nodes or among multiple nodes for broadcast communication. We realized that the shortest path problem has a wide application in the design of networks. Therefore, in this paper, we present a mesh network as our switching mechanism for computing the shortest path between the source and destination in our simulation model, developed using C++ on the Windows environment. The Floyd-Warshall algorithm is applied in finding the shortest path in all-pairs nodes.
ON THE SOLUTION OF TWO POINT BOUNDARY VALUE PROBLEMS WITH TWO POINT DIRECT METHOD
Authors: PHANG PEI SEE , MAJID ZANARIAH ABDUL , SULEIMAN MOHAMED
Published: April 2012

The two point boundary value problems (BVPs) occur in a wide variety of applications especially in sciences such as chemistry and biology. In this paper, we propose two point direct method of order six for solving nonlinear two point boundary value problems directly. This method is presented in a simple form of Adams Mouton type and determines the approximate solution at two point simultaneously. The method will be implemented using constant step size via shooting technique adapted with three-step iterative method. Numerical results are given to compare the efficiency of the proposed method with the Runge-Kutta and bvp4c method.
Exercise tames the wild side of the Myc network: a hypothesis
Authors: Gohil Kishorchandra , Brooks George A.
Published: April 2012

We propose that the well-documented therapeutic actions of repeated physical activities over human lifespan are mediated by the rapidly turning over proto-oncogenic Myc (myelocytomatosis) network of transcription factors. This transcription factor network is unique in utilizing promoter and epigenomic (acetylation/deacetylation, methylation/demethylation) mechanisms for controlling genes that include those encoding intermediary metabolism (the primary source of acetyl groups), mitochondrial functions and biogenesis, and coupling their expression with regulation of cell growth and proliferation. We further propose that remote functioning of the network occurs because there are two arms of this network, which consists of driver cells (e.g., working myocytes) that metabolize carbohydrates, fats, proteins, and oxygen and produce redox-modulating metabolites such as H2O2, NAD+, and lactate. The exercise-induced products represent autocrine, paracrine, or endocrine signals for target recipient cells (e.g., aortic endothelium, hepatocytes, and pancreatic β-cells) in which the metabolic signals are coupled with genomic networks and interorgan signaling is activated. And finally, we propose that lactate, the major metabolite released from working muscles and transported into recipient cells, links the two arms of the signaling pathway. Recently discovered contributions of the Myc network in stem cell development and maintenance further suggest that regular physical activity may prevent age-related diseases such as cardiovascular pathologies, cancers, diabetes, and neurological functions through prevention of stem cell dysfunctions and depletion with aging. Hence, regular physical activities may attenuate the various deleterious effects of the Myc network on health, the wild side of the Myc-network, through modulating transcription of genes associated with glucose and energy metabolism and maintain a healthy human status.
100 Years Since Scott Reached the Pole: A Century of Learning About the Physiological Demands of Antarctica
Authors: Halsey Lewis G. , Stroud Mike A.
Published: April 2012

The 1910–1913 Terra Nova Expedition to the Antarctic, led by Captain Robert Falcon Scott, was a venture of science and discovery. It is also a well-known story of heroism and tragedy since his quest to reach the South Pole and conduct research en route, while successful was also fateful. Although Scott and his four companions hauled their sledges to the Pole, they died on their return journey either directly or indirectly from the extreme physiological stresses they experienced. One hundred years on, our understanding of such stresses caused by Antarctic extremes and how the body reacts to severe exercise, malnutrition, hypothermia, high altitude, and sleep deprivation has greatly advanced. On the centenary of Scott's expedition to the bottom of the Earth, there is still controversy surrounding whether the deaths of those five men could have, or should have, been avoided. This paper reviews present-day knowledge related to the physiology of sustained man-hauling in Antarctica and contrasts this with the comparative ignorance about these issues around the turn of the 20th century. It closes by considering whether, with modern understanding about the effects of such a scenario on the human condition, Scott could have prepared and managed his team differently and so survived the epic 1,600-mile journey. The conclusion is that by carrying rations with a different composition of macromolecules, enabling greater calorific intake at similar overall weight, Scott might have secured the lives of some of the party, and it is also possible that enhanced levels of vitamin C in his rations, albeit difficult to achieve in 1911, could have significantly improved their survival chances. Nevertheless, even with today's knowledge, a repeat attempt at his expedition would by no means be bound to succeed.
EBV Reactivation and Chromosomal Polysomies:Euphorbia tirucallias a Possible Cofactor in Endemic Burkitt Lymphoma
Authors: Mannucci Susanna , Luzzi Anna , Carugi Alessandro , Gozzetti Alessandro , Lazzi Stefano , Malagnino Valeria , Simmonds Monique , Cusi Maria Grazia , Leoncini Lorenzo , van den Bosch Cornelia A. , De Falco Giulia
Published: April 2012

Burkitt lymphoma is endemic in the Equatorial Belt of Africa, its molecular hallmark is an activated,MYCgene mostly due to a chromosomal translocation. Especially in its endemic clinical variant, Burkitt lymphoma is associated with the oncogenic Epstein-Barr virus (EBV), and holoendemic malaria acts as an amplifier. Environmental factors may also cooperate in Burkitt lymphomagenesis in the endemic regions, such as plants used as traditional herbal remedies.Euphorbia tirucalli, a plant known to possess EBV-activating substances, has a similar geographical distribution to endemic Burkitt’s Lymphoma and is used as a hedge, herbal remedy and toy in the Lymphoma BeltI. In this study we aimed at determining if exposure toEuphorbia tirucallicould contribute to lymphomagenesis, and at which extent. Lymphoblastoid and cord blood-derived cell lines were treated with plant extracts, and the expression of EBV-coded proteins was checked, to assess EBV reactivation. The occurrence of chromosomal translocations was then investigated by FISH. Our preliminary results suggest thatE. tirucalliis able to reactivate EBV and determine chromosomal alterations, which leads to c-MYC altered expression. The existence of genomic alterations might determine the accumulation of further genetic alteration, which could eventually lead to a transformed phenotype.
Interleukin 28B Gene Polymorphism and Association with Chronic Hepatitis C Therapy Results in Latvia
Authors: Tolmane Ieva , Rozentale Baiba , Keiss Jazeps , Ivancenko Ludmila , Subnikova Nadezda , Reinholde Zaiga , Kozlovska Ieva , Sumlaninova Nina , Laivacuma Sniedze , Simanis Raimonds
Published: April 2012

Introduction. With the standard treatment of chronic hepatitis C, sustained virological response (SVR) can be achieved only in half of all patients. Interleukin-28B appears to be involved in the control of HCV infection, and the genetic polymorphism of the encoding IL-28B gene may determine the efficacy of clearance of HCV. The aim of this paper was to detect IL-28B gene polymorphism in Latvia and to analyze therapy results. This is the first study on IL-28B gene polymorphism in Latvia.
Material and Methods. There were 159 chronic viral hepatitis C patients included in the study. In order to detect IL-28B gene polymorphism, we used molecular biology techniques and methods: classical DNA separation, amplification by PCR, and standard sequencing. Genotype was defined as CC, CT, TC, or TT type. 142 patients were treated with the standard of care treatment. Results were analyzed according to IL-28B polymorphism. Results. There were 53 patients (33%) with CC genotype, 84 patients (53%) with CT/TC genotype, and 22 patients (14%) with TT genotype. 34 patients (74%) in CC genotype subgroup achieved SVR versus 50 patients (52%) in non-CC subgroups. In patients with genotype 1, SVR was achieved in 16 patients (84%) in CC subgroup versus 30 patients (47.6%) in non-CC subgroups, P=0.007. Conclusions. The most common genotype of IL28B in Latvia is CT/TC, with an incidence of 53%. Patients with CC genotype achieved SVR more often than CT or TT subgroups. IL28B gene polymorphism therefore is a strong predictor of treatment result.
The Interface between BCR-ABL-Dependent and -Independent Resistance Signaling Pathways in Chronic Myeloid Leukemia
Authors: Nestal de Moraes Gabriela , Souza Paloma Silva , Costas Fernanda Casal de Faria , Vasconcelos Flavia Cunha , Reis Flaviana Ruade Souza , Maia Raquel Ciuvalschi
Published: April 2012

Chronic myeloid leukemia (CML) is a clonal hematopoietic disorder characterized by the presence of the Philadelphia chromosome which resulted from the reciprocal translocation between chromosomes 9 and 22. The pathogenesis of CML involves the constitutive activation of the BCR-ABL tyrosine kinase, which governs malignant disease by activating multiple signal transduction pathways. The BCR-ABL kinase inhibitor, imatinib, is the front-line treatment for CML, but the emergence of imatinib resistance and other tyrosine kinase inhibitors (TKIs) has called attention for additional resistance mechanisms and has led to the search for alternative drug treatments. In this paper, we discuss our current understanding of mechanisms, related or unrelated to BCR-ABL, which have been shown to account for chemoresistance and treatment failure. We focus on the potential role of the influx and efflux transporters, the inhibitor of apoptosis proteins, and transcription factor-mediated signals as feasible molecular targets to overcome the development of TKIs resistance in CML.
Chinese Medicine Shenfu Injection for Heart Failure: A Systematic Review and Meta-Analysis
Authors: Wen-Ting Song , Fa-Feng Cheng , Li Xu , Cheng-Ren Lin , Jian-Xun Liu
Published: April 2012

Objective. Heart failure (HF) is a global public health problem. Early literature studies manifested that Shenfu injection (SFI) is one of the most commonly used traditional Chinese patent medicine for HF in China. This article intended to systematically evaluate the efficacy and safety of SFI for HF.Methods. An extensive search was performed within 6 English and Chinese electronic database up to November 2011. Ninety-nine randomized controlled trails (RCTs) were collected, irrespective of languages. Two authors extracted data and assessed the trial quality independently. RevMan 5.0.2 was used for data analysis.Results. Compared with routine treatment and/or device support, SFI combined with routine treatment and/or device support showed better effect on clinical effect rate, mortality, heart rate, NT-proBNP and 6-minute walk distance. Results in ultrasonic cardiography also showed that SFI combined with routine treatment improved heart function of HF patients. There were no significant difference in blood pressure between SFI and routine treatment groups. Adverse events were reported in thirteen trails with thirteen specific symptoms, while no serious adverse effect was reported.Conclusion. SFI appear to be effective for treating HF. However, further rigorously designed RCTs are warranted because of insufficient methodological rigor in the majority of included trials.
Pervasive Smart Spaces and Environments: A Service-Oriented Middleware Architecture for Wireless Ad Hoc and Sensor Networks
Authors: Familiar Miguel S. , Martínez José F. , López Lourdes
Published: April 2012

In the twenty-first century, the impact of wireless and ubiquitous technologies is changing the way people perceive and interact with the physical world. These communication paradigms promise to change and redefine, in a reasonably short period of time, the most common way of our everyday living. The continuous advances in the field of Wireless Sensor Networks and their direct application in Smart Spaces are clear examples of it. However, in order for this kind of new generation infrastructures to have a large-scale dissemination, there are still some open issues to tackle. In this way, this paper presents nSOM, a service-oriented framework based on sensor network design that provides internetworking services with the Internet cloud. This lightweight middleware architecture implements an agent-based virtual sensor service approach which is a compact semantic knowledge management scheme based on a dynamic composition model.
Reshuffling and Relocating: The Gendered and Income-Related Differential Effects of Restricting Smoking Locations
Authors: Hemsing Natalie , Greaves Lorraine , Poole Nancy , Bottorff Joan
Published: April 2012

This study investigates secondhand smoke (SHS) exposure and management in the context of smoking location restrictions, for nonsmokers, former, and current smokers. A purposive sample of 47 low income and non-low-income men and women of varied smoking statuses was recruited to participate in a telephone interview or a focus group. Amidst general approval of increased restrictions there were gendered patterns of SHS exposure and management, and effects of SHS policies that reflect power, control, and social roles that need to be considered as policies are developed, implemented and monitored. The experience of smoking restrictions and the management of SHS is influenced by the social context (relationship with a partner, family member, or stranger), the space of exposure (public or private, worksite), the social location of individuals involved (gender, income), and differential tolerance to SHS. This confluence of factors creates differing unintended and unexpected consequences to the social and physical situations of male and female smokers, nonsmokers, and former smokers. These factors deserve further study, in the interests of informing the development of future interventions and policies restricting SHS.
Modulation of Akt/mTOR Signaling Overcomes Sunitinib Resistance in Renal and Prostate Cancer Cells
Authors: Makhov Peter B. , Golovine Konstantin , Kutikov Alexander , Teper Ervin , Canter Daniel J. , Simhan Jay , Uzzo Robert G. , Kolenko Vladimir M.
Published: April 2012

Tyrosine kinase inhibitors exhibit impressive activity against advanced renal cell carcinoma. However, recent clinical studies have shown an equivocal response to sunitinib in patients with castration-resistant prostate cancer. The tumor suppressor PTEN acts as a gatekeeper of the phosphoinositide 3-kinase (PI3K)/Akt/mTOR cell–survival pathway. Our experiments showed that PTEN expression inversely correlates with sunitinib resistance in renal and prostate cancer cells. Restoration of PTEN expression markedly increases sensitivity of tumor cells to sunitinib both in vitro and in vivo. In addition, pharmacologic manipulation of PI3K/Akt/mTOR signaling with PI3K/mTOR inhibitor, GDC-0980, mTOR inhibitor, temsirolimus, or pan-Akt inhibitor, GSK690693, was able to overcome sunitinib resistance in cancer cells. Our findings underscore the importance of PTEN expression in relation to sunitinib resistance and imply a direct cytotoxic effect by sunitinib on tumor cells in addition to its antiangiogenic actions. Mol Cancer Ther; 11(7); 1510–7. ©2012 AACR.
Thermal Targeting of an Acid-Sensitive Doxorubicin Conjugate of Elastin-like Polypeptide Enhances the Therapeutic Efficacy Compared with the Parent Compound In Vivo
Authors: Moktan Shama , Perkins Eddie , Kratz Felix , Raucher Drazen
Published: April 2012

Elastin-like polypeptides (ELP) aggregate in response to mild hyperthermia, but remain soluble under normal physiologic conditions. ELP macromolecules can accumulate in solid tumors because of the enhanced permeability and retention effect. Tumor retention of ELPs can be further enhanced through hyperthermia-induced aggregation of ELPs by local heating of the tumor. We evaluated the therapeutic potential of ELPs in delivering doxorubicin in the E0771 syngeneic mouse breast cancer model. The ELP-Dox conjugate consisted of a cell-penetrating peptide at the N-terminus and the 6-maleimidocaproyl hydrazone derivative of doxorubicin at the C-terminus of ELP. The acid-sensitive hydrazone linker ensured release of doxorubicin in the lysosomes/endosomes after cellular uptake of the drug conjugate. ELP-Dox dosed at 5 mg doxorubicin equivalent/kg, extended the plasma half-life of doxorubicin to 5.5 hours. In addition, tumor uptake of ELP-Dox increased 2-fold when hyperthermia was applied, and was also enhanced compared to free doxorubicin. Although high levels of doxorubicin were found in the heart of animals treated with free doxorubicin, no detectable levels of doxorubicin were found in ELP-Dox–treated animals, indicating a correlation between tumor targeting and reduction of potential cardiac toxicity by ELP-Dox. At an optimal dose of 12 mg doxorubicin equivalent/kg, ELP-Dox in combination with hyperthermia induced a complete tumor growth inhibition, which was distinctly superior to free drug that only moderately inhibited tumor growth. In summary, our findings show that thermal targeting of ELP increases the potency of doxorubicin underlying the potential of exploiting ELPs to enhance the therapeutic efficacy of conventional anticancer drugs. Mol Cancer Ther; 11(7); 1547–56. ©2012 AACR.
Pemphigus Vulgaris of Skin: Cytological Findings and Pitfalls
Authors: Mokhtari Maral , Rasolmali Reza , Kumar Perikala Vijayananda
Published: April 2012

Background: Pemphigus vulgaris (PV) is an autoimmune bullous lesion of the skin and mucous membranes characterized by suprabasal clefting and acantholysis. The responsible autoantibody is desmoglein 3, a protein constituent of the desmosome. The diagnosis of PV is based on histological examination and immunofluorescence study. In addition, cytological smears could also be informative for the initial diagnosis of PV. Cases: Fifteen patients, 7 men and 8 women, with skin bullous disease clinically suspected of being PV were selected for cytological study. The bullae were ruptured and two smears were prepared from the fluid and stained with the Wright-Giemsa and Papanicolaou methods. The smears were taken from both new and old bullae. They showed acantholytic cells (Tzanck cells), some with amoeboid-like cytoplasmic projections, eosinophils, basophils, various forms of typical and atypical lymphocytes with irregular nuclear borders and cerebriform nuclei and dysplastic acantholytic cells with a high nucleo-cytoplasmic ratio and prominent nucleoli. The dysplastic cells were seen only in the old bullae. Histological examination and immunofluorescence study of the lesions confirmed the diagnosis of PV. Conclusion: PV can be diagnosed by cytology. Without a clinical history of PV, the presence of atypical lymphocytes and dysplastic cells may lead to a false diagnosis of malignancy.
Systematic Review, Meta-Analysis and Randomized Controlled Trials in Cytopathology
Authors: AbdullGaffar Badr
Published: April 2012

Objectives: Evidence-based medicine (EBM) relies on systematic review (SR), meta-analysis (MA) and randomized controlled trials (RCTs). These EBM tools are more commonly used in clinical medicine than in laboratory medicine. The extent of their use in cytopathology is not clear. The purpose of this study was to investigate the frequency of SR, MA and RCTs in cytopathology compared to other laboratory and clinical medicine specialties. Study Design: A literature-based search for SRs, MAs and RCTs in cytopathology was performed. Several electronic databases were searched without date restrictions. Four journals in cytopathology, pathology and clinical medicine were also searched over 6 years. Results: Gynecology cytology utilized SRs, MAs and RCTs more frequently (83%) than nongynecology and fine needle aspiration cytology. Cytopathology, histopathology and laboratory medicine journals showed comparable rates of 0.5–1.1% in papers reporting SRs, MAs and RCTs. Specialty medical journals showed a higher rate of 5.6% and general medical journals showed a much higher rate of 30%. Conclusions: SR, MA and RCTs are less frequently utilized in pathology than in clinical medicine. Cytopathologists should be more aware of the benefits of SR and MA in resolving uncertainties and improving the clinical applicability of level III diagnostic studies.
New Terminology for Intrauterine Endometrial Samples: A Group Study by the Japanese Society of Clinical Cytology
Authors: Yanoh Kenji , Hirai Yasuo , Sakamoto Atsuhiko , Aoki Daisuke , Moriya Takuya , Hiura Masamichi , Yamawaki Takaharu , Shimizu Keiko , Nakayama Hiroki , Sasaki Hiroshi , Tabata Tsutomu , Ueda Masatsugu , Udagawa Yasuhiro , Norimatsu Yoshiaki
Published: April 2012

Objective: To evaluate the sensitivity and specificity of endometrial cytology obtained by intrauterine sample using a descriptive reporting format for endometrial cytological diagnosis. Study Design: 10,152 consecutive endometrial scrapings obtained in 13 different Japanese hospitals were analyzed. Cytological results were classified as ‘negative for malignancy’, ‘atypical endometrial cells’ (ATEC), ‘endometrial hyperplasia’, ‘atypical endometrial hyperplasia’ or ‘malignant tumor’. ATEC was subclassified as ‘ATEC, of undetermined significance’ (ATEC-US) and ‘ATEC, cannot exclude atypical endometrial hyperplasia or more’ (ATEC-A). Cytological results were compared with the histological diagnosis as a gold standard. When the cytological result was ‘negative for malignancy’ and there was no subsequent histological examination, the case was considered a true negative when the endometrium was assessed as normal on transvaginal ultrasonography and there was no abnormal uterine bleeding. Results: 1,083 cases in which histology was not performed, 557 cases of ‘unsatisfactory specimen’ and 76 cases of ATEC-US were excluded. In the remaining 8,436 cases, the sensitivity and specificity, positive predictive value and negative predictive value for detecting atypical endometrial hyperplasia or malignant tumors were 79.0 and 99.7, 92.9 and 98.9%, respectively. Conclusion: The current diagnostic standards for endometrial cytology in Japan were established. Specificity is satisfactory for excluding cancer or precancerous diseases.
Vegetable Cell Contaminants in Urinary Bladder Diversion Cytology Specimens
Authors: Quiroga-Garza Gabriela , Nassar Diana , Khalbuss Walid E. , Monaco Sara E. , Pantanowitz Liron
Published: April 2012

Objective: We identified unique vegetable cell-like structures in urinary diversion specimens. This study aimed to describe their cytomorphology and prevalence and to investigate the possible origin of these contaminants. Study Design: A 10-year retrospective review of urinary diversion urine specimens with reported vegetable cell-like structures was performed. Data regarding patient demographics, previous history and specimen cytomorphology were recorded. To determine their prevalence, 100 urinary diversion cases were screened. Stoma materials were evaluated as possible contaminant sources. Results: A total of 11 urine cases from 7 patients (mean age 64 years; male/female ratio 2.5:1; all with ileal conduits) were identified with contaminating vegetable cell-like structures. These thick-walled cells contained dense, smudged cores and pericentral clearing. In 27% of cases, the specimens were less than optimal or unsatisfactory for evaluation due to low cellularity and associated lubricant material. No contaminating vegetable cell-like structures were found in the 100 screened cases. Stoma care products tested did not yield any morphologically similar structures. Conclusion: Vegetable cell-like structures may rarely be identified as a contaminant in urinary diversion specimens, possibly from stoma care material. Associated lubricant may affect specimen adequacy. These vegetable cell-like structures must be distinguished from true pathologic structures such as koilocytes or parasitic ova.
Natural Product Extract of Dicksonia sellowiana Induces Endothelium-Dependent Relaxations by a Redox-Sensitive Src- and Akt-Dependent Activation of eNOS in Porcine Coronary Arteries
Authors: Rattmann Yanna D. , Anselm Eric , Kim Jong-Hun , Dal-Ros Stéphanie , Auger Cyril , Miguel Obdulio G. , Santos Adair R.S. , Chataigneau Thierry , Schini-Kerth Valérie B.
Published: April 2012

Background/Aims: The consumption of polyphenol-rich food is associated with a decreased mortality from coronary diseases. This study examined whether a standardized hydroalcoholic extract of Dicksonia sellowiana (HEDS) triggered endothelium-dependent relaxations in porcine coronary artery rings and characterized the underlying mechanism. Methods: The phosphorylation level of Src, Akt and eNOS was assessed by Western blot analysis, the formation of reactive oxygen species by dihydroethidine staining and the level of eNOS Ser1177 phosphorylation by immunohistochemical staining in sections of coronary arteries. Results: HEDS-induced endothelium-dependent relaxations were strongly reduced by Nω-nitro-L-arginine, an eNOS inhibitor, and by its combination with charybdotoxin plus apamin, inhibitors of endothelium-derived hyperpolarizing factor-mediated responses. These relaxations were markedly reduced by MnTMPyP (a membrane-permeant mimetic of superoxide dismutase), polyethylene glycol catalase (PEG-catalase; a membrane-permeant analog of catalase), and by wortmannin (an inhibitor of PI3-kinase). HEDS-induced sustained phosphorylation of Akt and eNOS in endothelial cells was abolished by MnTMPyP, PEG-catalase and wortmannin. Oral administration of HEDS induced a significant decrease of mean arterial pressure in spontaneously hypertensive rats. Conclusion: These findings indicate that HEDS caused endothelium-dependent relaxations of coronary artery rings through the redox-sensitive activation of the endothelial PI3-kinase/Akt pathway leading to the subsequent activation of eNOS by phosphorylation. HEDS also has antihypertensive properties.
Detection of High-Grade Lesions on Cell Blocks from Residual Fluids of Pap Smears Diagnosed as Low-Grade Abnormalities: A Preliminary Pilot Study
Authors: Catteau Xavier , Simon Philippe , Noël Jean-Christophe
Published: April 2012

Objective: To investigate the feasibility of the technique of cell blocks (CBs) from residual fluids of Papanicolaou (Pap) smears diagnosed as low-grade abnormalities in the detection of high-grade lesions on biopsies. Study Design: In the present pilot study, we evaluated the sensitivity and specificity of 70 CBs from liquid-based cervicovaginal smears of women with atypical squamous cells (ASCs) of undetermined significance (ASCUS; n = 39), ASCs that cannot exclude high-grade squamous intraepithelial lesion (ASC-H; n = 17) and low-grade squamous intraepithelial lesions (LSILs; n = 14) in the detection of cervical intraepithelial neoplasia (CIN) type 2+ lesions. Results: Of the 70 CBs, 22 were diagnosed as negative, 27 as CIN1 and 21 as CIN2+. The sensitivity and specificity of CB preparation for the diagnosis of CIN2+ lesions were 50 and 100%, respectively, in ASCUS, 92 and 100%, respectively, in ASC-H, 100 and 100%, respectively, in LSILs. Conclusions: Our study confirms that CB preparation is a simple and reproducible technique with a good specificity that could be added advantageously to Pap smears to detect CIN2+ lesions in women with ASCs and LSILs.
Acetaldehyde at a Low Concentration Synergistically Exacerbates Allergic Airway Inflammation as an Endocrine-Disrupting Chemical and as a Volatile Organic Compound
Authors: Kawano Tetsuya , Matsuse Hiroto , Fukahori Susumu , Tsuchida Tomoko , Nishino Tomoya , Fukushima Chizu , Kohno Shigeru
Published: April 2012

Background: Acetaldehyde is an endocrine-disrupting chemical (EDC) and a volatile organic compound (VOC). It is also a carcinogen and teratogen that causes bronchoconstriction in a subset of asthmatics. However, the mechanism through which acetaldehyde acts as an EDC/VOC causing allergic airway inflammation remains unknown. Objectives: To determine the effects of a low concentration of acetaldehyde, which itself did not trigger airway inflammation, on extant allergic airway inflammation in a murine model of allergic asthma. Methods: We compared airway hyperresponsiveness (AHR), lung pathology, serum IgE and airway concentrations of cytokines among four groups of BALB/c mice [control, Dermatophagoides farinae(Df) allergen-sensitized (AS), intranasally acetaldehyde-injected (ALD) and AS-ALD mice]. Results: Physiological and histological differences were not evident between ALD and control mice. AS mice developed AHR and allergic airway inflammation characterized by goblet cell hyperplasia and eosinophilic infiltration. Both AHR and airway eosinophilia were significantly enhanced in AS-ALD compared with AS mice. Serum total and Df-specific IgE were significantly increased in both AS and AS-ALD mice compared with control and ALD mice, but comparable between AS and AS-ALD mice. Mite allergen sensitization significantly increased interleukin-5 and granulocyte macrophage colony-stimulating factor, and decreased interferon-γ levels in the airways; injecting acetaldehyde into airways with allergic inflammation significantly increased the levels of these inflammatory cytokines. Conclusions: Exposure to acetaldehyde can enhance allergic airway inflammation in asthma.
Etiological Classifications of Transient Ischemic Attacks: Subtype Classification by TOAST, CCS and ASCO – A Pilot Study
Authors: Amort Margareth , Fluri Felix , Weisskopf Florian , Gensicke Henrik , Bonati Leo H. , Lyrer Philippe A. , Engelter Stefan T.
Published: April 2012

Background: In patients with transient ischemic attacks (TIA), etiological classification systems are not well studied. The Trial of ORG 10172 in Acute Stroke Treatment (TOAST), the Causative Classification System (CCS), and the Atherosclerosis Small Vessel Disease Cardiac Source Other Cause (ASCO) classification may be useful to determine the underlying etiology. We aimed at testing the feasibility of each of the 3 systems. Furthermore, we studied and compared their prognostic usefulness. Methods: In a single-center TIA registry prospectively ascertained over 2 years, we applied 3 etiological classification systems. We compared the distribution of underlying etiologies, the rates of patients with determined versus undetermined etiology, and studied whether etiological subtyping distinguished TIA patients with versus without subsequent stroke or TIA within 3 months. Results: The 3 systems were applicable in all 248 patients. A determined etiology with the highest level of causality was assigned similarly often with TOAST (35.9%), CCS (34.3%), and ASCO (38.7%). However, the frequency of undetermined causes differed significantly between the classification systems and was lowest for ASCO (TOAST: 46.4%; CCS: 37.5%; ASCO: 18.5%; p < 0.001). In TOAST, CCS, and ASCO, cardioembolism (19.4/14.5/18.5%) was the most common etiology, followed by atherosclerosis (11.7/12.9/14.5%). At 3 months, 33 patients (13.3%, 95% confidence interval 9.3–18.2%) had recurrent cerebral ischemic events. These were strokes in 13 patients (5.2%; 95% confidence interval 2.8–8.8%) and TIAs in 20 patients (8.1%, 95% confidence interval 5.0–12.2%). Patients with a determined etiology (high level of causality) had higher rates of subsequent strokes than those without a determined etiology [TOAST: 6.7% (95% confidence interval 2.5–14.1%) vs. 4.4% (95% confidence interval 1.8–8.9%); CSS: 9.3% (95% confidence interval 4.1–17.5%) vs. 3.1% (95% confidence interval 1.0–7.1%); ASCO: 9.4% (95% confidence interval 4.4–17.1%) vs. 2.6% (95% confidence interval 0.7–6.6%)]. However, this difference was only significant in the ASCO classification (p = 0.036). Using ASCO, there was neither an increase in risk of subsequent stroke among patients with incomplete diagnostic workup (at least one subtype scored 9) compared with patients with adequate workup (no subtype scored 9), nor among patients with multiple causes compared with patients with a single cause. Conclusion: In TIA patients, all etiological classification systems provided a similar distribution of underlying etiologies. The increase in stroke risk in TIA patients with determined versus undetermined etiology was most evident using the ASCO classification.
Significance of Good Collateral Compensation in Symptomatic Intracranial Atherosclerosis
Authors: Lau Alexander Y.L. , Wong Edward H.C. , Wong Adrian , Mok Vincent C.T. , Leung Thomas W. , Wong Ka-sing Lawrence
Published: April 2012

Background: Collateral circulation stabilizes cerebral blood flow in patients with acute occlusion, but its prognostic role is less studied in intracranial atherosclerosis and appears different in moderate to severe stenosis. We aimed to study the associations between antegrade flow across stenosis, collateral flow via leptomeningeal anastomosis, and the neurological outcome and recurrence risk in patients with symptomatic intracranial stenosis. Methods: We examined a cohort of consecutive patients admitted for stroke or transient ischemic attack (TIA) with symptomatic intracranial stenosis confirmed by digital subtraction angiography in a single-center retrospective study. Angiograms were graded systematically in a blinded fashion for antegrade and collateral flow, using Thrombolysis in Cerebral Infarction (TICI) and American Society of Intervention and Therapeutic Neuroradiology/Society of Interventional Radiology (ASITN/SIR) grading, respectively, and integrated to a simple composite circulation score. Demographic and clinical variables, modified Rankin Scale (mRS) scores at 3 months, recurrent stroke or TIA in 12 months were collected. Uni- and multivariate analyses were performed to identify independent predictors of good outcome (mRS 0–2) and recurrence in a logistic regression model. Results: Among 69 patients with pure intracranial atherosclerosis ≥50%, compromised antegrade flow (TICI 0–2a) was observed in 26 (36%) patients and was associated with more severe arterial stenosis (mean 86 vs. 74%, p = 0.001). Poor collateral compensation resulting in a poor composite circulation score was observed in 8 (12%) patients. Patients with a good circulation score (n = 61, 88%) had preserved flow, which was associated with more favorable outcome (OR 7.50, 95% CI 1.11–50.7, p = 0.04) and less recurrent TIA or stroke (OR 0.18, 95% CI 0.04–0.96, p = 0.04). Prognosis was not significantly associated with antegrade or collateral grade per se. Conclusion: Good collateral compensations are more important in patients with symptomatic intracranial stenosis and compromised antegrade flow, and are associated with favorable outcome and less recurrence risk. The feasibility of composite flow assessment should be explored in future studies to identify high-risk intracranial stenosis with compromised hemodynamics.