bluuebunny/crossref_metadata_2025 huggingface dataset:
Liver stiffness measurement using transient elastography and hepatocellular carcinoma
Authors: Nakao Haruhisa , Yoneda Masashi
Published: September 2011

Liver fibrosis has been gaining noticeable attention because it may lead to end‐stage liver cirrhosis and ultimately to hepatocellular carcinoma. Thus, a precise estimation of the degree of liver fibrosis is crucial for predicting prognosis and deciding management of patients with chronic liver diseases. Many non‐invasive approaches for the evaluation of liver fibrosis have been developed. Among these procedures, transient elastography has recently drawn great attention. Transient elastography has been reported to be well correlated with the degree of liver fibrosis by many investigators and various institutions. Since the degree of liver fibrosis is considered as a strong predictor of risk for hepatocellular carcinoma development, several trials have been performed to verify the usefulness of measurement of liver stiffness to predict the emergence of hepatocellular carcinoma. From these studies, transient elastography seems to be a promising procedure to predict the risk of hepatocellular carcinoma; however, further cohorts with long‐term monitoring of liver stiffness are needed to confirm the usefulness of this method.
Influence of cigarette smoking on blood and salivary super oxide dismutase levels among smokers and non‐smokers
Authors: Reddy Sudhakara , Swapna Lingam Amara , Ramesh Tatipudi , Singh Takur Rajesh , Pradeep Koppolu
Published: September 2011

Aim:  To determine the influence of smoking on the blood and salivary superoxide dismutase levels among smokers, and to demonstrate the significance in alterations in the levels of superoxide dismutase in association with patient age, periodontal disease status, and duration and smoking frequency.

Methods:  Sixty healthy male patients (aged 20–60 years) constituted the target population. Blood and saliva samples were collected, and the periodontal index was measured using a Community Periodontal Index probe. Blood and salivary superoxide dismutase levels were calculated with the reagents prepared, and values were measured in a UV spectrophotometer.

Results:  There was a significant decrease in mean superoxide dismutase levels with an increase in age and smoking duration and frequency (0.23–0.05 U/mL). There was a range of 0.31–0.06 U/mL variation in the mean superoxide dismutase levels as the periodontal disease condition deteriorated.

Conclusions:  There was a significant reduction in the superoxide dismutase levels in the blood and saliva of smokers with increased duration and frequency of smoking, and as the periodontal disease condition worsened. Thus, this study emphasizes the importance of saliva as an easy, non‐invasive procedure in the diagnosis of patients who are more prone to precancerous lesions and conditions, and its importance in patient education and motivation programs for smoking cessation.
Pharmacists' perceptions of their practice: a comparison between Alberta and Northern Ireland
Authors: Al Hamarneh Yazid N , Rosenthal Meagen , McElnay James C , Tsuyuki Ross T
Published: September 2011

Objective

To explore how community pharmacists from Alberta, Canada, and Northern Ireland, UK, describe what a pharmacist does and to compare their responses.

Methods

Two hundred community pharmacists were interviewed using the telephone. The interviewer who introduced himself as a researcher asked two questions about the period over which the participants had been practising pharmacy and the way they describe what a pharmacist does. Responses were categorised into three categories: patient-centred, product-focused and ambiguous. Word-cloud analysis was used to assess the use of patient-care-related terms.

Key findings

Of the responses from community pharmacists in Alberta, 29% were categorised as patient-centred, 45% as product-focused and 26% as ambiguous. In Northern Ireland, 40% of the community pharmacists' responses were categorised as patient-centred, 39% as product-focused and 21% as ambiguous. Community pharmacists in Northern Ireland provided more patient-centred responses than community pharmacists in Alberta (P = 0.013). The word-cloud analysis showed that ‘medicine’ and ‘dispense’ were the most frequently reported terms. It also highlighted a relative lack of patient-care-related terms.

Conclusions

The findings of the present study are suggestive of some movement towards patient-centredness; however, product-focused practice still predominates within the pharmacy profession in Alberta and Northern Ireland. The relative lack of patient-care-related terms suggests that patient care is still not the first priority for pharmacists in both Alberta and Northern Ireland.
Dynamic changes in the perceived posture of the hand during ischaemic anaesthesia of the arm
Authors: Inui N. , Walsh L. D. , Taylor J. L. , Gandevia S. C.
Published: September 2011

Non‐technical summary  Even when the hand is stationary we know its position. This information is needed by the brain to plan movements. If the sensory input from a limb is removed through an accident, or an experiment with local anaesthesia, then a ‘phantom’ limb commonly develops. We used ischaemic anaesthesia of one arm to study the mechanisms which define the phantom hand. Surprisingly, if the wrist and fingers are held straight during anaesthesia, the perceived phantom hand becomes bent at the wrist and fingers, but if they are bent during anaesthesia, the final phantom is extended at the wrist and fingers. There is no ‘default’ posture for the phantom hand. Further, the hand appears to increase gradually in size as anaesthesia develops. The start of these perceptual changes occurs when input from large‐diameter sensory nerve fibres is declining. These results provide new information about how the brain generates phantom limbs.
Fuzzy Model Identification With Enhanced Validity Criterion for Mechanical System Design
Authors: Su Kuo-Ho
Published: September 2011

Model identification for machine system design, design optimization, and manufacturing planning is an important method that has high prediction accuracy and could become an essential stage in practical applications. In this paper, an effective fuzzy model identification algorithm for mechanical system design is developed. First, a fuzzy c-regression model clustering algorithm, in which hyperplane-shaped cluster representatives are utilized to provide a mathematical tool to partition the input–output space reasonably, is introduced. Then, an enhanced cluster validity criterion, in which the structural information hidden in the clusters can be reflected in the index, is proposed to choose the optimal number of clusters. In the proposed architecture, an improved Takagi–Sugeno fuzzy model is proposed to describe the system. Two illustrative examples under various conditions are provided, and their performances are indicated in comparison with other published works. In comparison to these fuzzy works, the proposed fuzzy model identification requires fewer fuzzy rules and a shorter tuning time.
Realization of an Arbitrary Planar Stiffness With a Simple Symmetric Parallel Mechanism
Authors: Huang Shuguang , Schimmels Joseph M.
Published: September 2011

This paper presents a new method for the realization of a planar compliant behavior with an elastic mechanism. The mechanisms considered are parallel with symmetric geometry. We show that any planar stiffness matrix can be realized using a parallel mechanism with four line springs connected symmetrically. Among the four springs, two are identical parallel springs equidistant from the stiffness center, and the other two identical springs intersect at the stiffness center. A synthesis procedure based on geometry is presented and mechanism compactness is discussed.
Surface-Affinity Profiling To Identify Host-Pathogen Interactions
Authors: Boleij Annemarie , Laarakkers Coby M. , Gloerich Jolein , Swinkels Dorine W. , Tjalsma Harold
Published: September 2011

Proteolytic treatment of intact bacterial cells has proven to be a convenient approach for the identification of surface-exposed proteins. This class of proteins directly interacts with the outside world, for instance, during adherence to human epithelial cells. Here, we aimed to identify host receptor proteins by introducing a preincubation step in which bacterial cells were first allowed to capture human proteins from epithelial cell lysates. Using
Streptococcus gallolyticus
as a model bacterium, liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis of proteolytically released peptides yielded the identification of a selective number of human epithelial proteins that were retained by the bacterial surface. Of these potential receptors for bacterial interference, (cyto)keratin-8 (CK8) was verified as the most significant hit, and its surface localization was investigated by subcellular fractionation and confocal microscopy. Interestingly, bacterial enolase could be assigned as an interaction partner of CK8 by MS/MS analysis of cross-linked protein complexes and complementary immunoblotting experiments. As surface-exposed enolase has a proposed role in epithelial adherence of several Gram-positive pathogens, its interaction with CK8 seems to point toward a more general virulence mechanism. In conclusion, our study shows that surface-affinity profiling is a valuable tool to identify novel adhesin-receptor pairs, which advocates its application in other hybrid biological systems.
Toll-Like Receptor 9 Modulates Macrophage Antifungal Effector Function during Innate Recognition of Candida albicans and Saccharomyces cerevisiae
Authors: Kasperkovitz Pia V. , Khan Nida S. , Tam Jenny M. , Mansour Michael K. , Davids Peter J. , Vyas Jatin M.
Published: September 2011

Phagocytic responses are critical for effective host defense against opportunistic fungal pathogens. Macrophages sample the phagosomal content and orchestrate the innate immune response. Toll-like receptor 9 (TLR9) recognizes unmethylated CpG DNA and is activated by fungal DNA. Here we demonstrate that specific triggering of TLR9 recruitment to the macrophage phagosomal membrane is a conserved feature of fungi of distinct phylogenetic origins, including
Candida albicans
,
Saccharomyces cerevisiae
,
Malassezia furfur
, and
Cryptococcus neoformans
. The capacity to trigger phagosomal TLR9 recruitment was not affected by a loss of fungal viability or cell wall integrity. TLR9 deficiency has been linked to increased resistance to murine candidiasis and to restriction of fungal growth
in vivo
. Macrophages lacking TLR9 demonstrate a comparable capacity for phagocytosis and normal phagosomal maturation compared to wild-type macrophages. We now show that TLR9 deficiency increases macrophage tumor necrosis factor alpha (TNF-α) production in response to
C. albicans
and
S. cerevisiae
, independent of yeast viability. The increase in TNF-α production was reversible by functional complementation of the TLR9 gene, confirming that TLR9 was responsible for negative modulation of the cytokine response. Consistently, TLR9 deficiency enhanced the macrophage effector response by increasing macrophage nitric oxide production. Moreover, microbicidal activity against
C. albicans
and
S. cerevisiae
was more efficient in TLR9 knockout (TLR9KO) macrophages than in wild-type macrophages. In conclusion, our data demonstrate that TLR9 is compartmentalized selectively to fungal phagosomes and negatively modulates macrophage antifungal effector functions. Our data support a model in which orchestration of antifungal innate immunity involves a complex interplay of fungal ligand combinations, host cell machinery rearrangements, and TLR cooperation and antagonism.
Perceptual cues in the regulation of exercise performance – physical sensations of exercise and awareness of effort interact as separate cues
Authors: Swart Jeroen , Lindsay Timothy Robert , Lambert Michael Ian , Brown James Craig , Noakes Timothy David
Published: September 2011

It has been argued that the physical sensations induced by exercise, measured as the ratings of perceived exertion (RPE), are distinct from the sense of effort. This study aimed to determine whether a new measure of task effort – the Task Effort and Awareness (TEA) score – is able to measure sensations distinct from those included in the conventional RPE scale. Seven well-trained cyclists completed a maximal effort 100 km time trial (TT) and a submaximal trial at 70% of the power sustained during the TT (70% TT). Five maximal 1 km sprints were included in both trials. Both the RPE related solely to physical sensation (P-RPE) and the TEA score increased during the TT and were linearly related. During the 70% TT, both P-RPE and TEA scores increased, but TEA increased significantly less than P-RPE (p<0.001). TEA scores reached maximal values in all 1 km sprints in both the maximal TT and 70% TT, whereas the RPE increased progressively, reaching a maximal value only in the final 1 km sprints in both the TT and the 70% TT. These results indicate that the physical sensations of effort measured as the P-RPE act as the template regulating performance during exercise and that deviation from that template produces an increase in the sense of effort measured by the TEA score. Together, these controls ensure that the chosen exercise intensity does not threaten bodily homeostasis. Our findings also explain why submaximal exercise conducted within the constraints of the template P-RPE does not produce any conscious awareness of effort.
Predictors of vibration perception threshold in type 2 diabetic patients with proliferative retinopathy
Authors: Magri Caroline Jane , Calleja Neville , Buhagiar Gerald , Fava Stephen , Vassallo Josanne
Published: September 2011

Purpose of the study

Distal peripheral neuropathy (DPN) is a troublesome complication of diabetes mellitus (DM). The factors associated with the disease are still incompletely understood. The purpose of this study was to investigate factors associated with vibration perception threshold (VPT) as a marker of DPN in a type 2 diabetic population with advanced microvascular disease.

Methods

The study included 203 diabetic patients (117 male, 86 female) with proliferative diabetic retinopathy. Subjects were investigated by questionnaires, clinical examinations, blood and urine sampling, and review of medical records in the period from November 2008 through April 2009. Presence of DPN was defined as VPT ≥25 V.

Results

The mean (±SD) age was 65.2 (±9.9) years and median (IQR) diabetes duration was 18 (10–25) years. Forty-six per cent of subjects were found to have DPN, defined as a VPT ≥25 V by neurothesiometer testing. Prevalence of DPN was found to be associated with age (p=0.038), male gender (p=0.046), low haemoglobin (p<0.001), high erythrocyte sedimentation rate (p=0.03), uric acid values (p=0.034), and peripheral vascular disease (PVD) (p=0.003) in univariate analysis. Multivariate logistic regression analysis revealed male gender (OR 5.52; p<0.001) and low haemoglobin values (B=−0.58; p<0.001) to be independent predictors of VPT ≥25 V in subjects with proliferative retinopathy, while linear regression analysis revealed male gender (p<0.001), haemoglobin (p=0.001), age (p=0.04), and PVD (p=0.001) to be significant predictors of VPT.

Conclusions

This study reports a novel independent association of DPN with low haemoglobin values. In the study population with type 2 DM and proliferative retinopathy, DPN was also independently associated with male gender, age, and PVD. Further studies are needed to confirm the association with low haemoglobin and identify the underlying mechanism.
TILTED BIANCHI TYPE-V BAROTROPIC FLUID COSMOLOGICAL MODELS WITH VARIABLE BULK VISCOSITY IN GENERAL RELATIVITY
Authors: BALI RAJ , KUMAWAT PRAMILA , SHARMA SHALINI
Published: September 2011

Tilted Bianchi type-V barotropic fluid cosmological models with heat conduction and variable bulk viscosity is investigated. To get the deterministic model of the universe, we have assumed two conditions: (i) A = (BC)nand (ii) ζθ = const where A, B, C are metric potentials, n is a constant, ζ the coefficient of bulk viscosity, θ the expansion in the model. The behavior of the model in presence and absence of bulk viscosity and singularities in the model are discussed. Some thermodynamic relations and physical aspects of the model related to the observation on the present day universe are also discussed.
Preparation of States in Open Quantum Mechanics
Authors: Modi Kavan
Published: September 2011

We study preparation of states for open quantum mechanics. For non-Markovian systems that are initially correlated with the environment, the effects of the preparation procedure are nontrivial. This is due to the indirect effects on the state of the environment induced via the correlations with the system and the act of preparation on the system. We give three concrete examples of preparation procedure to elucidate our claims.
MULTISCALE MODELING OF THE POROELASTIC PROPERTIES OF VARIOUS OIL-WELL CEMENT PASTES
Authors: GHABEZLOO SIAVASH
Published: September 2011

Evaluation of the poroelastic properties of oil-well cement paste is essential for prediction of the performance of the cement sheath during the life of a well. A multiscale homogenization model is used to evaluate the poroelastic properties of different classes of oil-well cement paste. The model has been calibrated in a previous work based on the results of a laboratory study on a hardened class G cement paste. A hydration model is used to evaluate the volume fractions of different microstructure phases of cement paste based on the chemical composition of clinker and the water-to-cement ratio. Typical chemical compositions of API class A to class H oil-well cements with their corresponding water-to-cement ratios are used to evaluate the poroelastic parameters such as drained bulk modulus, Biot coefficient, Skempton coefficient, etc. The results show that the difference in the chemical compositions of these cements has not an important effect on the variations of the poroelastic properties. Contrarily, the water-to-cement ratio has an important effect on the variations of these parameters.
The Minimal Failure-Causing Schema of Combinatorial Testing
Authors: Nie Changhai , Leung Hareton
Published: September 2011

Combinatorial Testing (CT) involves the design of a small test suite to cover the parameter value combinations so as to detect failures triggered by the interactions among these parameters. To make full use of CT and to extend its advantages, this article first gives a model of CT and then presents a theory of the Minimal Failure-causing Schema (MFS), including the concept of the MFS, proof of its existence, some of its properties, and a method of finding the MFS. Then we propose a methodology for CT based on this MFS theory and the existing research. Our MFS-based methodology emphasizes that CT should work on accurate testing requirements, and has the following advantages: 1) Detect failure to the greatest degree with the least cost. 2) Effectiveness is improved by emphasizing mining of the information in software and making full use of the information gained from test design and execution. 3) Determine the root causes of failures and reveal related faults near the exposed ones. 4) Provide a foundation and model for regression testing and software quality evaluation of CT. A case study is presented to illustrate the MFS-based CT methodology, and an empirical study on a real software developed by us shows that the MFS really exists and the methodology based on MFS can considerably improve CT.
All-pairs shortest paths with a sublinear additive error
Authors: Roditty Liam , Shapira Asaf
Published: September 2011

We show that, for every 0 ≤
p
≤ 1, there is an
O
(
n

2.575−
p
/(7.4−2.3
p
)

)-time algorithm that given a directed graph with small positive integer weights, estimates the length of the shortest path between every pair of vertices
u
,
v
in the graph to within an additive error δ

p

(
u
,
v
), where δ(
u
,
v
) is the exact length of the shortest path between
u
and
v
. This algorithm runs faster than the fastest algorithm for computing exact shortest paths for any 0 <
p
≤ 1.

Previously the only way to “beat” the running time of the exact shortest path algorithms was by applying an algorithm of Zwick [2002] that approximates the shortest path distances within a multiplicative error of (1 + ϵ). Our algorithm thus gives a smooth qualitative and quantitative transition between the fastest
exact
shortest paths algorithm, and the fastest approximation algorithm with a linear additive error. In fact, the main ingredient we need in order to obtain the above result, which is also interesting in its own right, is an algorithm for computing (1 + ϵ) multiplicative approximations for the shortest paths, whose running time is faster than the running time of Zwick's approximation algorithm when ϵ ≪ 1 and the graph has small integer weights.
Anomalous Geomagnetic Variations Possibly Linked with the Taiwan Earthquake (Mw=6.4) on 19 December 2009
Authors: Takla E. M. , Yumoto K. , Liu J. Y. , Kakinami Y. , Uozumi T. , Abe S. , Ikeda A.
Published: September 2011

On 19 December 2009, the eastern part of Taiwan at approximate depth of 45 km was struck by a strong earthquake (Mw=6.4). The epicenter was located about 20 km away from the Hualien (HLN) station in Taiwan. By analyzing data from the HLN station and Amami Oshima (AMA) in Japan as a remote reference, the geomagnetic east-west (D) and vertical (Z) components recorded at the HLN station are showing no correlation with those at the AMA station in December 2009. Anomalous variations of ∼10–15 nT started about one week before the occurrence of the earthquake and lasted for about two weeks. Also, an enhanced ULF signal in the range of Pc 3 (10–40 s) was observed a few days before the onset of the earthquake. Moreover, the polarization ratio (Z/H (north-south component)) of the Pc 3 amplitude at the HLN station decreased a few days preceding the earthquake. The mechanism behind these anomalous variations is not fully understood. However, we expect that crustal stress perturbations and underground conductivity changes associated with the earthquake played an important role for generating such observed geomagnetic variations.
Neutrophil Degranulation and Immunosuppression in Patients with GBM: Restoration of Cellular Immune Function by Targeting Arginase I
Authors: Sippel Trisha R. , White Jason , Nag Kamalika , Tsvankin Vadim , Klaassen Marci , Kleinschmidt-DeMasters B.K. , Waziri Allen
Published: September 2011

Purpose: The source of glioblastoma (GBM)-associated immunosuppression remains multifactorial. We sought to clarify and therapeutically target myeloid cell–derived peripheral immunosuppression in patients with GBM.

Experimental Design: Direct ex vivo T-cell function, serum Arginase I (ArgI) levels, and circulating myeloid lineage populations were compared between patients with GBM and normal donors or patients with other intracranial tumors. Immunofunctional assays were conducted using bulk and sorted cell populations to explore the potential transfer of myeloid cell–mediated immunosuppression and to identify a potential mechanism for these effects. ArgI-mediated immunosuppression was therapeutically targeted in vitro through pharmacologic inhibition or arginine supplementation.

Results: We identified a significantly expanded population of circulating, degranulated neutrophils associated with elevated levels of serum ArgI and decreased T-cell CD3ζ expression within peripheral blood from patients with GBM. Sorted CD11b+ cells from patients with GBM were found to markedly suppress normal donor T-cell function in coculture, and media harvested from mitogen-stimulated GBM peripheral blood mononuclear cell (PBMC) or GBM-associated mixed lymphoid reactions showed ArgI levels that were significantly higher than controls. Critically, T-cell suppression in both settings could be completely reversed through pharmacologic ArgI inhibition or with arginine supplementation.

Conclusions: These data indicate that peripheral cellular immunosuppression in patients with GBM is associated with neutrophil degranulation and elevated levels of circulating ArgI, and that T-cell function can be restored in these individuals by targeting ArgI. These data identify a novel pathway of GBM-mediated suppression of cellular immunity and offer a potential therapeutic window for improving antitumor immunity in affected patients. Clin Cancer Res; 17(22); 6992–7002. ©2011 AACR.
Phase I Trial of Adoptive Cell Transfer with Mixed-Profile Type-I/Type-II Allogeneic T Cells for Metastatic Breast Cancer
Authors: Hardy Nancy M. , Mossoba Miriam E. , Steinberg Seth M. , Fellowes Vicki , Yan Xiao-Yi , Hakim Frances T. , Babb Rebecca R. , Avila Daniele , Gea-Banacloche Juan , Sportès Claude , Levine Bruce L. , June Carl H. , Khuu Hahn M. , Carpenter Ashley E. , Krumlauf Michael C. , Dwyer Andrew J. , Gress Ronald E. , Fowler Daniel H. , Bishop Michael R.
Published: September 2011

Purpose: Metastatic breast cancer (MBC) response to allogeneic lymphocytes requires donor T-cell engraftment and is limited by graft-versus-host disease (GVHD). In mice, type-II–polarized T cells promote engraftment and modulate GVHD, whereas type-I–polarized T cells mediate more potent graft-versus-tumor (GVT) effects. This phase I translational study evaluated adoptive transfer of ex vivo costimulated type-I/type-II (T1/T2) donor T cells with T-cell–depleted (TCD) allogeneic stem cell transplantation (AlloSCT) for MBC.

Experimental Design: Patients had received anthracycline, taxane, and antibody therapies, and been treated for metastatic disease and a human leukocyte antigen (HLA)-identical–sibling donor. Donor lymphocytes were costimulated ex vivo with anti-CD3/anti-CD28 antibody–coated magnetic beads in interleukin (IL)-2/IL-4–supplemented media. Patients received reduced intensity conditioning, donor stem cells and T1/T2 cells, and monitoring for toxicity, engraftment, GVHD, and tumor response; results were compared with historical controls, identically treated except for T1/T2 product infusions.

Results: Mixed type-I/type-II CD4+ T cells predominated in T1/T2 products. Nine patients received T1/T2 cells at dose level 1 (5 × 106 cells/kg). T-cell donor chimerism reached 100% by a median of 28 days. Seven (78%) developed acute GVHD. At day +28, five patients had partial responses (56%) and none had MBC progression; thereafter, two patients had continued responses. Donor T-cell engraftment and tumor responses appeared faster than in historical controls, but GVHD rates were similar and responders progressed early, often following treatment of acute GVHD.

Conclusion: Allogeneic T1/T2 cells were safely infused with TCD-AlloSCT, appeared to promote donor engraftment, and may have contributed to transient early tumor responses. Clin Cancer Res; 17(21); 6878–87. ©2011 AACR.
Reassessment of sst5 Somatostatin Receptor Expression in Normal and Neoplastic Human Tissues Using the Novel Rabbit Monoclonal Antibody UMB-4
Authors: Lupp Amelie , Hunder Anna , Petrich Aline , Nagel Falko , Doll Christian , Schulz Stefan
Published: September 2011

Objective: The frequent overexpression of somatostatin receptors (sst) in neuroendocrine tumors provides the molecular basis for the diagnostic and therapeutic application of stable somatostatin analogs. Whereas octreotide acts mainly via the sst2 receptor, the novel pan-somatostatin analog pasireotide exhibits particular high affinity for the sst5 receptor. To determine whether a patient is a candidate for octreotide or pasireotide therapy, it is important to evaluate the somatostatin receptor status. However, so far highly specific rabbit monoclonal antibodies have been developed for the sst2 receptor only (clone UMB-1). Methods: Here, we have extensively characterized a novel rabbit monoclonal antibody for the human sst5 receptor (clone UMB-4). In a comparative immunohistochemical study, the expression of sst5 and sst2 receptors was assessed using UMB-4 and UMB-1, respectively. Results: Western blot experiments unequivocally demonstrated that UMB-4 selectively detected its cognate sst5 receptor and did not cross-react with other proteins present in crude tissue homogenates. UMB-4 yielded a highly effective immunostaining of distinct cell populations in formalin-fixed, paraffin-embedded human tissues with a predominance of plasma membrane staining. In the pituitary, sst5 was present on all growth hormone (GH)- and adrenocorticotropin hormone (ACTH)-producing cells whereas sst2 was only observed on a subpopulation of GH-positive cells. Consequently, sst5 was detectable on the majority of GH and ACTH adenomas. In contrast, sst2 was only seen on GH but not on ACTH adenomas. Conclusions:The rabbit monoclonal antibodies UMB-4 and UMB-1 will facilitate the assessment of the somatostatin receptor status of human tumors during routine histopathological examinations.
A Novel Role for an Endothelial Adrenergic Receptor System in Mediating Catecholestradiol-Induced Proliferation of Uterine Artery Endothelial Cells
Authors: Jobe Sheikh O. , Fling Sean N. , Ramadoss Jayanth , Magness Ronald R.
Published: September 2011

Sequential conversion of estradiol-17β to its biologically active catecholestradiols, 2-hydroxyestradiol (OHE
2
) and 4-OHE
2
, contributes importantly to its angiogenic effects on uterine artery endothelial cells (UAECs) derived from pregnant, but not nonpregnant ewes via an estrogen receptor-independent mechanism. Because catecholestradiols and catecholamines exhibit structural similarities and have high affinity for α- and β-adrenergic receptors (ARs), we investigated whether the endothelial α- or β-ARs mediate catecholestradiol-induced proliferation of P-UAECs and whether catecholamines alter these responses. Western analyses revealed expression of specific AR subtypes in nonpregnant UAECs and P-UAECs, including α
2
-, β
2
-, and β
3
-ARs but not α
1
- and β
1
-ARs. Levels of β
2
-ARs and β
3
-ARs were unaltered by pregnancy, whereas α
2
-ARs were decreased. Norepinephrine and epinephrine increased P-UAEC, but not nonpregnant UAEC proliferation, and these effects were suppressed by propranolol (β-AR blocker) but not phentolamine (α-AR blocker). Catecholamines combinations with 2-OHE
2
or 4-OHE
2
enhanced P-UAEC mitogenesis. Catecholestradiol-induced P-UAEC proliferation was also inhibited by propranolol but not phentolamine. β
2
-AR and β
3
-AR antagonists (ICI 118 551and SR 59230A, respectively) abrogated the mitogenic effects of both 2-OHE
2
and 4-OHE
2
. Stimulation of β
2
-ARs and β
3
-ARs using formoterol and BRL 37344 dose-dependently stimulated P-UAEC proliferation, which was abrogated by ICI 118 551 and SR 59230A, respectively. Proliferation effects of both catecholamines and catecholestradiols were only observed in P-UAECs (not nonpregnant UAECs) and were mediated via β
2
-ARs and β
3
-ARs. We demonstrate for the first time convergence of the endothelial AR and estrogenic systems in regulating endothelial proliferation, thus providing a distinct evolutionary advantage for modulating uterine perfusion during stressful pregnancies.
Profibrotic potential of Prominin-1+epithelial progenitor cells in pulmonary fibrosis
Authors: Blyszczuk Przemyslaw , Germano Davide , Stein Sokrates , Moch Holger , Matter Christian M , Beck-Schimmer Beatrice , Lüscher Thomas F , Eriksson Urs , Kania Gabriela
Published: September 2011

Background

In idiopathic pulmonary fibrosis loss of alveolar epithelium induces inflammation of the pulmonary tissue followed by accumulation of pathogenic myofibroblasts leading eventually to respiratory failures. In animal models inflammatory and resident cells have been demonstrated to contribute to pulmonary fibrosis. Regenerative potential of pulmonary and extra-pulmonary stem and progenitor cells raised the hope for successful treatment option against pulmonary fibrosis. Herein, we addressed the contribution of lung microenvironment and prominin-1+ bone marrow-derived epithelial progenitor cells in the mouse model of bleomycin-induced experimental pulmonary fibrosis.

Methods

Prominin-1+ bone marrow-derived epithelial progenitors were expanded from adult mouse lungs and differentiated in vitro by cytokines and growth factors. Pulmonary fibrosis was induced in C57Bl/6 mice by intratracheal instillation of bleomycin. Prominin-1+ progenitors were administered intratracheally at different time points after bleomycin challenge. Green fluorescence protein-expressing cells were used for cell tracking. Cell phenotypes were characterized by immunohistochemistry, flow cytometry and quantitative reverse transcription-polymerase chain reaction.

Results

Prominin-1+ cells expanded from healthy lung represent common progenitors of alveolar type II epithelial cells, myofibroblasts, and macrophages. Administration of prominin-1+ cells 2 hours after bleomycin instillation protects from pulmonary fibrosis, and some of progenitors differentiate into alveolar type II epithelial cells. In contrast, prominin-1+ cells administered at day 7 or 14 lose their protective effects and differentiate into myofibroblasts and macrophages. Bleomycin challenge enhances accumulation of bone marrow-derived prominin-1+ cells within inflamed lung. In contrast to prominin-1+ cells from healthy lung, prominin-1+ precursors isolated from inflamed organ lack regenerative properties but acquire myofibroblast and macrophage phenotypes.

Conclusion

The microenvironment of inflamed lung impairs the regenerative capacity of bone marrow-derived prominin-1+ progenitors and promotes their differentiation into pathogenic phenotypes.
Three-dimensional reconstructions of intrahepatic bile duct tubulogenesis in human liver
Authors: Vestentoft Peter S , Jelnes Peter , Hopkinson Branden M , Vainer Ben , Møllgård Kjeld , Quistorff Bjørn , Bisgaard Hanne C
Published: September 2011

Background

During liver development, intrahepatic bile ducts are thought to arise by a unique asymmetric mode of cholangiocyte tubulogenesis characterized by a series of remodeling stages. Moreover, in liver diseases, cells lining the Canals of Hering can proliferate and generate new hepatic tissue. The aim of this study was to develop protocols for three-dimensional visualization of protein expression, hepatic portal structures and human hepatic cholangiocyte tubulogenesis.

Results

Protocols were developed to digitally visualize portal vessel branching and protein expression of hepatic cell lineage and extracellular matrix deposition markers in three dimensions. Samples from human prenatal livers ranging from 7 weeks + 2 days to 15½ weeks post conception as well as adult normal and acetaminophen intoxicated liver were used. The markers included cytokeratins (CK) 7 and 19, the epithelial cell adhesion molecule (EpCAM), hepatocyte paraffin 1 (HepPar1), sex determining region Y (SRY)-box 9 (SOX9), laminin, nestin, and aquaporin 1 (AQP1).

Digital three-dimensional reconstructions using CK19 as a single marker protein disclosed a fine network of CK19 positive cells in the biliary tree in normal liver and in the extensive ductular reactions originating from intrahepatic bile ducts and branching into the parenchyma of the acetaminophen intoxicated liver. In the developing human liver, three-dimensional reconstructions using multiple marker proteins confirmed that the human intrahepatic biliary tree forms through several developmental stages involving an initial transition of primitive hepatocytes into cholangiocytes shaping the ductal plate followed by a process of maturation and remodeling where the intrahepatic biliary tree develops through an asymmetrical form of cholangiocyte tubulogenesis.

Conclusions

The developed protocols provide a novel and sophisticated three-dimensional visualization of vessels and protein expression in human liver during development and disease.
Whole-exome sequencing of DNA from peripheral blood mononuclear cells (PBMC) and EBV-transformed lymphocytes from the same donor
Authors: Londin Eric R , Keller Margaret A , D'Andrea Michael R , Delgrosso Kathleen , Ertel Adam , Surrey Saul , Fortina Paolo
Published: September 2011

Background

The creation of lymphoblastoid cell lines (LCLs) through Epstein-Barr virus (EBV) transformation of B-lymphocytes can result in a valuable biomaterial for cell biology research and a renewable source of DNA. While LCLs have been used extensively in cellular and genetic studies, the process of cell transformation and expansion during culturing may introduce genomic changes that may impact their use and the interpretation of subsequent genetic findings.

Results

We performed whole exome sequencing on a tetrad family using DNA derived from peripheral blood mononuclear cells (PBMCs) and LCLs from each individual. We generated over 4.7 GB of mappable sequence to a 125X read coverage per sample. An average of 19,354 genetic variants were identified. Comparison of the two DNA sources from each individual showed an average concordance rate of 95.69%. By lowering the variant calling parameters, the concordance rate between the paired samples increased to 99.82%. Sanger sequencing of a subset of the remaining discordant variants did confirm the presence of de novo mutations arising in LCLs.

Conclusions

By varying software stringency parameters, we identified 99% concordance between DNA sequences derived from the two different sources from the same donors. These results suggest that LCLs are an appropriate representation of the genetic material of the donor and suggest that EBV transformation can result in low-level generation of de novo mutations. Therefore, use of PBMC or early passage EBV-transformed cells is recommended. These findings have broad-reaching implications, as there are thousands of LCLs in public biorepositories and individual laboratories.
Semiallogenic fusions of MSI+tumor cells and activated B cells induce MSI-specific T cell responses
Authors: Garbe Yvette , Klier Ulrike , Linnebacher Michael
Published: September 2011

Background

Various strategies have been developed to transfer tumor-specific antigens into antigen presenting cells in order to induce cytotoxic T cell responses against tumor cells. One approach uses cellular vaccines based on fusions of autologous antigen presenting cells and allogeneic tumor cells. The fusion cells combine antigenicity of the tumor cell with optimal immunostimulatory capacity of the antigen presenting cells.

Microsatellite instability caused by mutational inactivation of DNA mismatch repair genes results in translational frameshifts when affecting coding regions. It has been shown by us and others that these mutant proteins lead to the presentation of immunogenic frameshift peptides that are - in principle - recognized by a multiplicity of effector T cells.

Methods

We chose microsatellite instability-induced frameshift antigens as ideal to test for induction of tumor specific T cell responses by semiallogenic fusions of microsatellite instable carcinoma cells with CD40-activated B cells. Two fusion clones of HCT116 with activated B cells were selected for stimulation of T cells autologous to the B cell fusion partner. Outgrowing T cells were phenotyped and tested in functional assays.

Results

The fusion clones expressed frameshift antigens as well as high amounts of MHC and costimulatory molecules. Autologous T cells stimulated with these fusions were predominantly CD4+, activated, and reacted specifically against the fusion clones and also against the tumor cell fusion partner. Interestingly, a response toward 6 frameshift-derived peptides (of 14 tested) could be observed.

Conclusion

Cellular fusions of MSI+ carcinoma cells and activated B cells combine the antigen-presenting capacity of the B cell with the antigenic repertoire of the carcinoma cell. They present frameshift-derived peptides and can induce specific and fully functional T cells recognizing not only fusion cells but also the carcinoma cells. These hybrid cells may have great potential for cellular immunotherapy and this approach should be further analyzed in preclinical as well as clinical trials. Moreover, this is the first report on the induction of frameshift-specific T cell responses without the use of synthetic peptides.
Use of silver nanoparticles increased inhibition of cell-associated HIV-1 infection by neutralizing antibodies developed against HIV-1 envelope proteins
Authors: Lara Humberto H , Ixtepan-Turrent Liliana , Garza Treviño Elsa N , Singh Dinesh K
Published: September 2011

Background

HIV/AIDS pandemic is a worldwide public health issue. There is a need for new approaches to develop new antiviral compounds or other therapeutic strategies to limit viral transmission. The envelope glycoproteins gp120 and gp41 of HIV are the main targets for both silver nanoparticles (AgNPs) and neutralizing antibodies. There is an urgency to optimize the efficiency of the neutralizing antibodies (NABs). In this study, we demonstrated that there is an additive effect between the four NABs and AgNPs when combined against cell-associated HIV-1 infection in vitro

Results

Four NABs (Monoclonal antibody to HIV-1 gp41 126-7, HIV-1 gp120 Antiserum PB1 Sub 2, HIV-1 gp120 Antiserum PB1, HIV-1 gp120 Monoclonal Antibody F425 B4e8) with or without AgNPs of 30-50 nm in size were tested against cell free and cell-associated HIVIIIB virus. All NABs inhibited HIV-1 cell free infection at a dose response manner, but with AgNPs an antiviral additive effect was not achieved Although there was no inhibition of infection with cell-associated virus by the NABs itself, AgNPs alone were able to inhibit cell associated virus infection and more importantly, when mixed together with NABs they inhibited the HIV-1 cell associated infection in an additive manner.

Discussion

The most attractive strategies to deal with the HIV problem are the development of a prophylactic vaccine and the development of effective topical vaginal microbicide. For two decades a potent vaccine that inhibits transmission of infection of HIV has been searched. There are vaccines that elicit NABs but none of them has the efficacy to stop transmission of HIV-1 infection. We propose that with the addition of AgNPs, NABs will have an additive effect and become more potent to inhibit cell-associated HIV-1 transmission/infection.

Conclusions

The addition of AgNPs to NABs has significantly increased the neutralizing potency of NABs in prevention of cell-associated HIV-1 transmission/infection. Further exploration is required to standardize potentiation of NABs by AgNPs. It is also required to evaluate in vivo toxicity of AgNPs before AgNPs could be incorporated in any antiviral vaginal creams.
Evaluation of triblock copolymeric micelles of δ- valerolactone and poly (ethylene glycol) as a competent vector for doxorubicin delivery against cancer
Authors: Nair K Lekha , Jagadeeshan Sankar , Nair S Asha , Kumar G S Vinod
Published: September 2011

Background

Specific properties of amphiphilic copolymeric micelles like small size, stability, biodegradability and prolonged biodistribution have projected them as promising vectors for drug delivery. To evaluate the potential of δ-valerolactone based micelles as carriers for drug delivery, a novel triblock amphiphilic copolymer poly(δ-valerolactone)/poly(ethylene glycol)/poly(δ-valerolactone) (VEV) was synthesized and characterized using IR, NMR, GPC, DTA and TGA. To evaluate VEV as a carrier for drug delivery, doxorubicin (DOX) entrapped VEV micelles (VEVDMs) were prepared and analyzed for in vitro antitumor activity.

Results

VEV copolymer was successfully synthesized by ring opening polymerization and the stable core shell structure of VEV micelles with a low critical micelle concentration was confirmed by proton NMR and fluorescence based method. Doxorubicin entrapped micelles (VEVDMs) prepared using a modified single emulsion method were obtained with a mean diameter of 90 nm and high encapsulation efficiency showing a pH dependent sustained doxorubicin release. Biological evaluation in breast adenocarcinoma (MCF7) and glioblastoma (U87MG) cells by flow cytometry showed 2-3 folds increase in cellular uptake of VEVDMs than free DOX. Block copolymer micelles without DOX were non cytotoxic in both the cell lines. As evaluated by the IC50 values VEVDMs induced 77.8, 71.2, 81.2% more cytotoxicity in MCF7 cells and 40.8, 72.6, 76% more cytotoxicity in U87MG cells than pristine DOX after 24, 48, 72 h treatment, respectively. Moreover, VEVDMs induced enhanced apoptosis than free DOX as indicated by higher shift in Annexin V-FITC fluorescence and better intensity of cleaved PARP. Even though, further studies are required to prove the efficacy of this formulation in vivo the comparable G2/M phase arrest induced by VEVDMs at half the concentration of free DOX confirmed the better antitumor efficacy of VEVDMs in vitro.

Conclusions

Our studies clearly indicate that VEVDMs possess great therapeutic potential for long-term tumor suppression. Furthermore, our results launch VEV as a promising nanocarrier for an effective controlled drug delivery in cancer chemotherapy.
A tool to measure the attributes of receiving IV therapy in a home versus hospital setting: the Multiple Sclerosis Relapse Management Scale (MSRMS)
Authors: Riazi Afsane , Porter Bernadette , Chataway Jeremy , Thompson Alan J , Hobart Jeremy C
Published: September 2011

Background

Intravenous steroids are routinely used to treat disabling relapses in multiple sclerosis (MS). Theoretically, the infusion could take place at home, rather than in hospital. Findings from other patient populations suggest that patients may find the experiences of home relapse management more desirable. However, formal comparison of these two settings, from the patients' point of view, was prevented by the lack of a clinical scale. We report the development of a rating scale to measure patient's experiences of relapse management that allowed this question to be answered confidently.

Methods

Scale development had three stages. First, in-depth interviews of 21 MS patients generated a conceptual model and pool of potential scale items. Second, these items were administered to 160 people with relapsing-remitting MS. Standard psychometric techniques were used to develop a scale. Third, the psychometric properties of the scale were evaluated in a randomised controlled trial of 138 patients whose relapses were managed either at home or hospital.

Results

A preliminary conceptual model with eight dimensions, and a pool of 154 items was generated. From this we developed the MS Relapse Management Scale (MSRMS), a 42-item with four subscales: access to care (6 items), coordination of care (11 items), information (7 items), interpersonal care (18 items). The MSRMS subscales satisfied most psychometric criteria but had notable floor effects.

Conclusions

The MSRMS is a reliable and valid measure of patients' experiences of MS relapse management. The high floor effects suggest most respondents had positive care experiences. Results demonstrate that patients' experiences of relapse management can be measured, and that the MSRMS is a powerful tool for determining which services to develop, support and ultimately commission.