bluuebunny/crossref_metadata_2025 huggingface dataset:
PKC-δ sensitizes Kir3.1/3.2 channels to changes in membrane phospholipid levels after M3 receptor activation in HEK-293 cells
Authors: Brown Sean G. , Thomas Alison , Dekker Lodewijk V. , Tinker Andrew , Leaney Joanne L.
Published: April 2005

G protein-gated inward rectifier (Kir3) channels are inhibited by activation of Gq/11-coupled receptors and this has been postulated to involve the signaling molecules protein kinase C (PKC) and/or phosphatidylinositol 4,5-bisphosphate (PIP2). Their precise roles in mediating the inhibition of this family of channels remain controversial. We examine here their relative roles in causing inhibition of Kir3.1/3.2 channels stably expressed in human embryonic kidney (HEK)-293 cells after muscarinic M3 receptor activation. In perforated patch mode, staurosporine prevented the Gq/11-mediated, M3 receptor, inhibition of channel activity. Recovery from M3-mediated inhibition was wortmannin sensitive. Whole cell currents, where the patch pipette was supplemented with PIP2, were still irreversibly inhibited by M3 receptor stimulation. When adenosine A1 receptors were co-expressed, inclusion of PIP2 rescued the A1-mediated response. Recordings from inside-out patches showed that catalytically active PKC applied directly to the intracellular membrane face inhibited the channels: a reversible effect modulated by okadaic acid. Generation of mutant heteromeric channel Kir3.1S185A/Kir3.2C-S178A, still left the channel susceptible to receptor, pharmacological, and direct kinase-mediated inhibition. Biochemically, labeled phosphate is incorporated into the channel. We suggest that PKC-δ mediates channel inhibition because recombinant PKC-δ inhibited channel activity, M3-mediated inhibition of the channel, was counteracted by overexpression of two types of dominant negative PKC-δ constructs, and, by using confocal microscopy, we have demonstrated translocation of green fluorescent protein-tagged PKC-δ to the plasma membrane on M3 receptor stimulation. Thus Kir3.1/3.2 channels are sensitive to changes in membrane phospholipid levels but this is contingent on the activity of PKC-δ after M3 receptor activation in HEK-293 cells.
Lack of pyloric interstitial cells of Cajal explains distinct peristaltic motor patterns in stomach and small intestine
Authors: Wang Xuan-Yu , Lammers Wim J. E. P. , Bercik Premysl , Huizinga Jan D.
Published: April 2005

The frequency and propagation velocity of distension-induced peristaltic contractions in the antrum and duodenum are distinctly different and depend on activation of intrinsic excitatory motoneurons as well as pacemaker cells, the interstitial cells of Cajal associated with Auerbach's plexus (ICC-AP). Because ICC are critical for coordination of motor activities along the long axis of many regions in the gut, the role of ICC in antroduodenal coordination was investigated. We used immunohistochemistry, electron microscopy, simultaneous multiple electrical recordings in vitro, and videofluoroscopy in vivo in mice and rats. A strongly reduced number of ICC-AP with loss of network characteristics was observed in a 4-mm area in the rat and a 1-mm area in the mouse pyloric region. The pyloric region showed a slow wave-free gap of 4.1 mm in rats and 1.3 mm in mice. Between antrum and duodenum, there was no interaction of electrical activities and in the absence of gastric emptying, there was no coordination of motor activities. When the pyloric sphincter opened, 2.4 s before the front of the antral wave reached the pylorus, the duodenum distended after receiving gastric content and aboral duodenal peristalsis was initiated, often disrupting other motor patterns. The absence of ICC-AP and slow wave activity in the pyloric region allows the antrum and duodenum to have distinct uncoordinated motor activities. Coordination of aborally propagating peristaltic antral and duodenal activity is initiated by opening of the pylorus, which is followed by distention-induced duodenal peristalsis. Throughout this coordinated motor activity, the pacemaker systems in antrum and duodenum remain independent.
Leptin enhances feeding suppression and neural activation produced by systemically administered bombesin
Authors: Ladenheim Ellen E. , Emond M. , Moran T. H.
Published: April 2005

Leptin amplifies feeding inhibition and neural activation produced by either cholecystokinin or intragastric preloads, suggesting that leptin may increase the efficacy of gastrointestinal meal-related signals. To determine whether leptin would similarly potentiate the feeding inhibitory actions of another putative satiety peptide, we evaluated the effects of third ventricular leptin administration on food intake and c-Fos activation in response to systemically administered bombesin (BN). Leptin (3.5 μg) was administered 1 h before either 0.9% saline or BN (0.32 and 1.0 nmol/kg) followed by 30-min access to Ensure liquid diet. Although neither leptin nor 0.32 nmol/kg BN alone suppressed Ensure intake, the combination reduced intake by 28%. The higher BN dose (1.0 nmol/kg) produced a significant suppression by itself but was further enhanced in the presence of leptin. Consistent with the behavioral results, c-Fos activation in the nucleus of the solitary tract was increased by combined dosages of leptin and 0.32 nmol/kg BN beyond the individual response to either peptide. In the presence of leptin, BN produced a 3.4- to 5.2-fold increase in the number of c-Fos-positive cells in the nucleus of the solitary tract compared with when BN was given alone. These data provide further support for the hypothesis that the effect of leptin on food intake may be mediated, in part, by modulating meal-related satiety signals.
AICAR and hyperosmotic stress increase insulin-stimulated glucose transport
Authors: Smith Jill L. , Patil Pankaj B. , Fisher Jonathan S.
Published: April 2005

Sensitivity of glucose transport to stimulation by insulin has been shown to occur concomitant with activation of the AMP-activated protein kinase (AMPK) in skeletal muscle, suggesting a role of AMPK in regulation of insulin action. The purpose of the present study was to evaluate a possible role of AMPK in potentiation of insulin action in muscle cells. The experimental model involved insulin-responsive C2C12 myotubes that exhibit a twofold increase in glucose transport in the presence of insulin. Treatment of myotubes with the AMPK activator 5-aminoimidazole-4-carboxamide-1-β-d-ribofuranoside (AICAR), followed by a 2-h recovery, augmented the ability of insulin to stimulate glucose transport. Similarly, incubation in hyperosmotic medium, another AMPK-activating treatment, acted synergistically with insulin to stimulate glucose transport. Furthermore, the increase in insulin action caused by hyperosmotic stress was prevented by inclusion of compound C, an AMPK inhibitor, in hyperosmotic medium. In addition, iodotubercidin, a general kinase inhibitor that is effective against AMPK, also prevented the combined effects of insulin and hyperosmotic stress on glucose transport. The new information provided by these data is that previously reported AICAR effects on insulin action are generalizable to myotubes, hyperosmotic stress and insulin synergistically increase glucose transport, and AMPK appears to mediate potentiation of insulin action.
Visuospatial Memory Computations During Whole-Body Rotations in Roll
Authors: Van Pelt S. , Van Gisbergen J.A.M. , Medendorp W. P.
Published: April 2005

We used a memory-saccade task to test whether the location of a target, briefly presented before a whole-body rotation in roll, is stored in egocentric or in allocentric coordinates. To make this distinction, we exploited the fact that subjects, when tilted sideways in darkness, make systematic errors when indicating the direction of gravity (an allocentric task) even though they have a veridical percept of their self-orientation in space. We hypothesized that if spatial memory is coded allocentrically, these distortions affect the coding of remembered targets and their readout after a body rotation. Alternatively, if coding is egocentric, updating for body rotation becomes essential and errors in performance should be related to the amount of intervening rotation. Subjects ( n = 6) were tested making saccades to remembered world-fixed targets after passive body tilts. Initial and final tilt angle ranged between −120° CCW and 120° CW. The results showed that subjects made large systematic directional errors in their saccades (up to 90°). These errors did not occur in the absence of intervening body rotation, ruling out a memory degradation effect. Regression analysis showed that the errors were closely related to the amount of subjective allocentric distortion at both the initial and final tilt angle, rather than to the amount of intervening rotation. We conclude that the brain uses an allocentric reference frame, possibly gravity-based, to code visuospatial memories during whole-body tilts. This supports the notion that the brain can define information in multiple frames of reference, depending on sensory inputs and task demands.
Slow and Fast Inhibition and an H-Current Interact to Create a Theta Rhythm in a Model of CA1 Interneuron Network
Authors: Rotstein Horacio G. , Pervouchine Dmitri D. , Acker Corey D. , Gillies Martin J. , White John A. , Buhl Eberhardt H. , Whittington Miles A. , Kopell Nancy
Published: April 2005

The oriens-lacunosum moleculare (O-LM) subtype of interneuron is a key component in the formation of the theta rhythm (8–12 Hz) in the hippocampus. It is known that the CA1 region of the hippocampus can produce theta rhythms in vitro with all ionotropic excitation blocked, but the mechanisms by which this rhythmicity happens were previously unknown. Here we present a model suggesting that individual O-LM cells, by themselves, are capable of producing a single-cell theta-frequency firing, but coupled O-LM cells are not capable of producing a coherent population theta. By including in the model fast-spiking (FS) interneurons, which give rise to IPSPs that decay faster than those of the O-LM cells, coherent theta rhythms are produced. The inhibition to O-LM cells from the FS cells synchronizes the O-LM cells, but only when the FS cells themselves fire at a theta frequency. Reciprocal connections from the O-LM cells to the FS cells serve to parse the FS cell firing into theta bursts, which can then synchronize the O-LM cells. A component of the model O-LM cell critical to the synchronization mechanism is the hyperpolarization-activated h-current. The model can robustly reproduce relative phases of theta frequency activity in O-LM and FS cells.
An example for a one‐parameter nonexpansive semigroup
Authors: Suzuki Tomonari
Published: April 2005

We give one example for a one‐parameter nonexpansive semigroup.
This example shows that there exists a one‐parameter nonexpansive
semigroup {T(t) : t ≥ 0} on a closed convex subset C of a Banach space E such that
for some x ∈ C, which is not a common fixed point of {T(t) : t ≥ 0}.
Higher-order Nielsen numbers
Authors: Saveliev Peter
Published: April 2005

Suppose "Equation missing", "Equation missing" are manifolds, "Equation missing" are maps. The well-known coincidence problem studies the coincidence set "Equation missing". The number "Equation missing" is called the codimension of the problem. More general is the preimage problem. For a map "Equation missing" and a submanifold "Equation missing" of "Equation missing", it studies the preimage set "Equation missing", and the codimension is "Equation missing". In case of codimension "Equation missing", the classical Nielsen number "Equation missing" is a lower estimate of the number of points in "Equation missing" changing under homotopies of "Equation missing", and for an arbitrary codimension, of the number of components of "Equation missing". We extend this theory to take into account other topological characteristics of "Equation missing". The goal is to find a "lower estimate" of the bordism group "Equation missing" of "Equation missing". The answer is the Nielsen group "Equation missing" defined as follows. In the classical definition, the Nielsen equivalence of points of "Equation missing" based on paths is replaced with an equivalence of singular submanifolds of "Equation missing" based on bordisms. We let "Equation missing", then the Nielsen group of order "Equation missing" is the part of "Equation missing" preserved under homotopies of "Equation missing". The Nielsen number "Equation missing" of order "Equation missing" is the rank of this group (then "Equation missing"). These numbers are new obstructions to removability of coincidences and preimages. Some examples and computations are provided.
Convergence theorems for fixed points of demicontinuous pseudocontractive mappings
Authors: Chidume CE , Zegeye H
Published: April 2005

Let "Equation missing" be an open subset of a real uniformly smooth Banach space "Equation missing". Suppose "Equation missing" is a demicontinuous pseudocontractive mapping satisfying an appropriate condition, where "Equation missing" denotes the closure of "Equation missing". Then, it is proved that (i) "Equation missing" for every "Equation missing"; (ii) for a given "Equation missing", there exists a unique path "Equation missing", "Equation missing", satisfying "Equation missing". Moreover, if "Equation missing" or there exists "Equation missing" such that the set "Equation missing" is bounded, then it is proved that, as "Equation missing", the path "Equation missing" converges strongly to a fixed point of "Equation missing". Furthermore, explicit iteration procedures with bounded error terms are proved to converge strongly to a fixed point of "Equation missing".
Approximating zero points of accretive operators with compact domains in general Banach spaces
Authors: Miyake Hiromichi , Takahashi Wataru
Published: April 2005

We prove strong convergence theorems of Mann's type and Halpern's type for resolvents of accretive operators with compact domains and apply these results to find fixed points of nonexpansive mappings in Banach spaces.
Reliability for some bivariate gamma distributions
Authors: Nadarajah Saralees
Published: April 2005

In the area of stress‐strength models, there has been a large
amount of work as regards estimation of the reliability R = Pr(X < Y). The algebraic form for R = Pr(X < Y) has
been worked out for the vast majority of the well‐known
distributions when X and Y are independent random
variables belonging to the same univariate family. In this
paper, we consider forms of R when (X, Y) follows a
bivariate distribution with dependence between X and Y. In
particular, we derive explicit expressions for R when the
joint distribution is bivariate gamma. The calculations
involve the use of special functions.
Set differential equations with causal operators
Authors: Drici Z. , Mcrae F. A. , Devi J. Vasundhara
Published: April 2005

We obtain some basic results on existence, uniqueness, and
continuous dependence of solutions with respect to initial values
for set differential equations with causal operators.
About a stress deformation condition of a piecewise‐uniform wedge with a systemof collinear cracks at an antiplane deformation
Authors: Bardzokas D. I. , Gevorgyan S. H. , Mkhitaryan S. M.
Published: April 2005

An antiplane problem of a stress deformation condition of a
piecewise wedge
consisting of two heterogeneous wedges with different opening
angles and containing on the line of their attachment a system of
arbitrary finite number of collinear cracks is investigated. With
the help of Mellin′s integral transformation the problem is
brought to the solution of the singular integral equation relating
to the density of the displacement dislocation on the
cracks, which then is reduced to a system of singular integral
equations with kernels being represented in the form of sums of
Cauchy kernels and
regular kernels. This system of equations is solved by the known
numerical method. Stress intensity factors (SIF) are calculated
and the behavior of characteristic geometric and physical
parameters is revealed. Besides, the density of the displacement
dislocation on the cracks, their evaluation, and J
‐integrals are
calculated.
NAD(P)H Oxidase–Dependent Self-Propagation of Hydrogen Peroxide and Vascular Disease
Authors: Cai Hua
Published: April 2005

Excessive production of reactive oxygen species in the vasculature contributes to cardiovascular pathogenesis. Among biologically relevant and abundant reactive oxygen species, superoxide (O
2
·−
) and hydrogen peroxide (H
2
O
2
) appear most important in redox signaling. Whereas O
2
·−
predominantly induces endothelial dysfunction by rapidly inactivating nitric oxide (NO
·
), H
2
O
2
influences different aspects of endothelial cell function via complex mechanisms. This review discusses recent advances establishing a critical role of H
2
O
2
in the development of vascular disease, in particular, atherosclerosis, and mechanisms whereby vascular NAD(P)H oxidase–derived H
2
O
2
amplifies its own production. Recent studies have shown that H
2
O
2
stimulates reactive oxygen species production via enhanced intracellular iron uptake, mitochondrial damage, and sources of vascular NAD(P)H oxidases, xanthine oxidase, and uncoupled endothelial nitric oxide synthase (eNOS). This self-propagating phenomenon likely prolongs H
2
O
2
-dependent pathological signaling in vascular cells, thus contributing to vascular disease development. The latest progress on Nox functions in vascular cells is also discussed [Nox for
N
AD(P)H
ox
idases, representing a family of novel NAD(P)H oxidases].
Emotional and Temporal Aspects of Situation Model Processing during Text Comprehension: An Event-Related fMRI Study
Authors: Ferstl Evelyn C. , Rinck Mike , Cramon D. Yves von
Published: April 2005

Language comprehension in everyday life requires the continuous integration of prior discourse context and general world knowledge with the current utterance or sentence. In the neurolinguistic literature, these so-called situation model building processes have been ascribed to the prefrontal cortex or to the right hemisphere. In this study, we use whole-head event-related fMRI to directly map the neural correlates of narrative comprehension in context. While being scanned using a spin-echo sequence, 20 participants listened to 32 short stories, half of which contained globally inconsistent information. The inconsistencies concerned either temporal or chronological information or the emotional status of the protagonist. Hearing an inconsistent word elicited activation in the right anterior temporal lobe. The comparison of different information aspects revealed activation in the left precuneus and a bilateral frontoparietal network for chronological information. Emotional information elicited activation in the ventromedial prefrontal cortex and the extended amygdaloid complex. In addition, the integration of inconsistent emotional information engaged the dorsal frontomedial cortex (Brodmann's area 8/9), whereas the integration of inconsistent temporal information required the lateral prefrontal cortex bilaterally. These results indicate that listening to stories can elicit activation reflecting content-specific processes. Furthermore, updating of the situation model is not a unitary process but it also depends on the particular requirements of the text. The right hemisphere contributes to language processing in context, but equally important are the left medial and bilateral prefrontal cortices.
“Kids Need Structure”
Authors: Armaline William T.
Published: April 2005

This study illuminates aspects of social life within agencies designed to house homeless adolescents through research conducted at a live-in, emergency youth shelter. The shelter provides physical necessities, safety, life skills, and a “consistent” social environment through its operationas a quasi-total institution. Social life within the shelter is characterized by constant negotiation of the curricular imposition of “structure.” External boundaries become more or less permeable as a result of the degrees to which shelter residents and staff challenge or conform to rules meant to define them. Shelter curriculum may be critiqued for treating adolescent homelessness as an individual rather than social problem, where rules simultaneously emphasize the modification of individual behaviors and serve as social control mechanisms. Shelter residents, whose poverty and homelessness are only marginally connected to personal behaviors or choices, mount (at times) conscious opposition to rules sanctioning their personal freedoms and access to the outside world.
Sharing Neighborhoods
Authors: Farrell Chad R.
Published: April 2005

The presence of homeless persons in or near residential areas has been characterized as a marker of encroaching urban disorder that undermines neighborhood quality and engenders fear among residents. Using data compiled from a national survey, the author tests these assumptions by assessing how residential exposure to homelessness influences domiciled respondents. Those who encounter a neighborhood homeless presence or who live near shelters are likely to witness a range of disorderly and orderly behaviors on the part of homeless persons. These residents tend to view homelessness as a large and growing community problem but do not attribute neighborhood decline to the homeless themselves. Contrary to disorder perspectives, residential exposure to homelessness is unrelated to fear among residents.
Danger on the Streets
Authors: Lee Barrett A. , Schreck Christopher J.
Published: April 2005

Data from a national survey are used to examine the relationship between marginality and criminal victimization among the homeless. The results show that homeless people are victimized disproportionately often both in absolute and relative terms (i.e., compared to members of the domiciled population)and that the modal pattern entails multiple forms of victimization. Conventional demographic antecedents of victimization receive little support in the analysis. However, measures representing different dimensions of marginality—disaffiliation, health problems, traumatic events, and lifestyle-exposure—all significantly increase the odds of being victimized, as hypothesized. The failure of the lifestyle-exposure variables to mediate the effects of the other predictors suggests that distal factors should be considered along with proximate ones if the vulnerability of disadvantaged groups to crime is to be adequately understood. Implications of the present research for the victim-offender relationship and the meaning of victimization are also discussed.
Managing Service Demand
Authors: Radas Sonja , Shugan Steven M.
Published: April 2005

This article shows that although not-for-profit services may find that demand-shifting strategies are effective, these strategies usually offer no improvement in profits. These strategies are, therefore, ineffective for private service providers who seek to improve profits. It is better for these private service providers to eliminate excess demand during peak periods than to attempt to shift some of this demand to the off-peak period. For-profit service providers should, instead, focus on demand-stimulating strategies. The authors show that bundling strategies that manage demand by combining peak with off-peak service delivery can be very profitable. Increases in price during the peak period have a greater impact on profits than increases in demand during the off-peak period because, when operating at maximum capacity, the greatest profits are achieved.
Under-reporting of inpatient services utilisation in household surveys – a population-based study in Hong Kong
Authors: Tsui Eva LH , Leung Gabriel M , Woo Pauline PS , Choi Sarah , Lo Su-Vui
Published: April 2005

Background

Recognising that household interviews may produce biased estimates of health services utilisation, we examined for under- and over-reporting of hospitalisation episodes in three recent, consecutive population-based household surveys in Hong Kong.

Methods

Territory-wide inpatient service utilisation volumes as estimated from the 1999, 2001 and 2002 Thematic Household Surveys (THS) were benchmarked against corresponding statistics derived from routine administrative databases. Between-year differences on net under-reporting were quantified by Cohen's d effect size. To assess the potential for systematic biases in under-reporting, age- and sex-specific net under-reporting rates within each survey year were computed and the F-test was performed to evaluate differences between demographic subgroups. We modelled the effects of age and sex on the likelihood of ever hospitalisation through logistic regression to compare the odds ratios respectively derived from survey and administrative data.

Results

The extent of net under-reporting was moderately large in all three years amounting to about one-third of all inpatient episodes. However, there did not appear to be significant systematic biases in the degree of under-reporting by age or sex on stratified analyses and logistic regression modelling.

Conclusion

Under-reporting was substantial in Hong Kong's THS. Recall bias was likely most responsible for such reporting inaccuracies. A proper full-design record-check study should be carried out to confirm the present findings.
Dietary omega-3 fatty acids and ionizing irradiation on human breast cancer xenograft growth and angiogenesis
Authors: Hardman W Elaine , Sun LuZhe , Short Nicholas , Cameron Ivan L
Published: April 2005

Background

The effects of an omega-3 (n-3) fatty acid enriched diet alone and in combination with gamma irradiation (IR) therapy in nude mice bearing a human MDA-MB231 breast cancer xenograft were tested. The cancer cells were injected into the mammary fat pad of young female mice. Six weeks later, mice were randomly divided into two diet groups: 1) mice with 10% corn oil (rich in omega 6 fatty acids) in their food, 2) mice consuming a 10% fat diet that was enriched in n-3 fatty acids. After two weeks on the diet, treatment with 200 cGy of IR every second day for four treatments (total 800 cGy) was initiated on half of the mice from each diet group. Some mice in each of the 4 groups were euthanized 24 hours after the end of IR while the remaining mice were followed for 3 additional weeks. Tumor sections were stained for endothelial cells with CD31 and PAS and for hypoxia inducible factor 1α (HIF-α).

Results

The tumor cortex within 100 microns of the well-vascularized capsule had little vascularization. Blood vessels, capillaries, and endothelial pseudopods were found at areas greater than 100 microns from the capsule (subcortex). Mice on the corn oil diet and treated with IR 24 hours previously or non-irradiated mice fed the n-3 diet had tumors with fewer blood vessels in the subcortex and more endothelial pseudopods projecting into hypoxic (HIF- α positive) areas than did mice from the non-irradiated corn oil fed group. The tumor growth rate of mice that received IR or that were fed the n-3 fatty acid enriched diet was significantly slower than in the mice fed the 10% corn oil diet. Harmful side effects were found only in the IR treated mice.

Conclusion

The omega-3 fatty acid enriched diet proved to be a safe means for retarding tumor growth and vascularization.
Adoptive T cell therapy: Addressing challenges in cancer immunotherapy
Authors: Yee Cassian
Published: April 2005

Adoptive T cell therapy involves the ex vivo selection and expansion of effector cells for the treatment of patients with cancer. In this review, the advantages and limitations of using antigen-specific T cells are discussed in counterpoint to vaccine strategies. Although vaccination strategies represent more readily available reagents, adoptive T cell therapy provides highly selected T cells of defined phenotype, specificity and function that may influence their biological behavior in vivo. Adoptive T cell therapy offers not only translational opportunities but also a means to address fundamental issues in the evolving field of cancer immunotherapy.
Differential expression of CCR3 and CXCR3 by human lung and bone marrow-derived mast cells: implications for tissue mast cell migration
Authors: Brightling Christopher E , Kaur Davinder , Berger Patrick , Morgan Angela J , Wardlaw Andrew J , Bradding Peter
Published: April 2005

The selective microlocalization of mast cells within specific airway structures, such as the airway smooth muscle and submucosal glands, in asthma is important in the pathophysiology of inflammatory lung disease. Chemokines are likely candidates mediating mast cell migration into these tissue compartments. In this study, we have defined the chemokine receptor profile of human lung mast cells (HLMC) compared with mast cells derived from human bone marrow (BM) and the human mast cell line HMC-1. CXC chemokine receptor 3 (CXCR3) was the most highly expressed chemokine receptor on ex vivo HLMC analyzed by flow cytometry, and CXCR3 expression by mast cells in the bronchial mucosa was confirmed by immuno-histochemistry. CXCR3 was functional, inducing a rise in cytosolic-free Ca2+, actin reorganization, and chemotaxis in response to the CXC ligands CXCL9, -10, and -11. CXCR3 activation did not induce degranulation or cytokine synthesis. In addition, more than 10% of ex vivo HLMC expressed CC chemokine receptor 3, CXCR1, and CXCR4. It is interesting that CXCR3 was not expressed by human BM-derived mast cells, suggesting its expression is induced during tissue maturation. As CXCR3 ligands are elevated in many pulmonary diseases, CXCR3 may be important for determining the anatomical microlocalization of mast cells within the human lung.
Lipopolysaccharide stimulation converts vigorously washed dendritic cells (DCs) to nonexhausted DCs expressing CD70 and evoking long-lasting type 1 T cell responses
Authors: Iwamoto Sanju , Ishida Makoto , Takahashi Keiko , Takeda Ken , Miyazaki Akira
Published: April 2005

A great variety of in vitro culture protocols for human monocyte-derived dendritic cells (mo-DCs) has been used to generate DCs suitable for use in immunotherapy. It is thought that activated DCs undergo one-way differentiation into “exhausted” DCs. In the present study, we contrived an in vitro method for facilitating expression of CD70 by mature DCs. This was achieved by vigorous washing of mo-DCs before exposure to lipopolysaccharide (LPS). Unexpectedly, these mature DCs retain expression of some interleukin (IL)-12 family members after extended periods and maintain their ability to stimulate type 1 T cell responses. In contrast, DCs exposed to IL-4 before LPS stimulation or LPS-stimulated DCs not exposed to washing stress before activation failed to express CD70 and did differentiate into exhausted DCs. It is interesting that DCs expressing CD70 (CD70+ DCs) induced interferon-γ production from purified, allogeneic CD8+ T cells through a direct CD27-CD70 interaction. This is evidence for a pathway resulting in generation of CD8 T effectors by B7-independent mechanisms. These data suggest that exposure of immature DCs to LPS stimulation contributes to their terminal differentiation into CD70+ DCs, which have potent ability to prolong type 1 T cell responses through alternative pathways.
Enhanced TLR4 reactivity following injury is mediated by increased p38 activation
Authors: Maung Adrian A , Fujimi Satoshi , Miller Marissa L , MacConmara Malcolm P , Mannick John A , Lederer James A
Published: April 2005

Severe injury primes the innate-immune system for increased Toll-like receptor 4 (TLR4)-induced proinflammatory cytokine production by macrophages. In this study, we examined changes in TLR4 signaling pathways in splenic macrophages from burn-injured or sham mice to determine the molecular mechanism(s) responsible for the increased TLR4 responsiveness. Using flow cytometry and specific antibodies, we first looked for injury-induced changes in the expression levels of several TLR-associated signaling molecules. We found similar levels of myeloid differentiation primary-response protein 88 (MyD88) and interleukin-1 receptor-associated kinase-M (IRAK-M) and somewhat lower levels of total p38, extracellular signal-regulated kinase (ERK), and stress-activated protein kinase (SAPK)/c-jun N-terminal kinase (JNK) mitogen-activated protein kinases (MAPKs) in burn compared with sham macrophages. However, with the use of antibodies specific for the phosphorylated (activated) forms of the three MAPKs, we found that macrophages from burn mice showed a twofold increase in purified lipopolysaccharide (LPS)-stimulated p38 activation as compared with cells from sham mice on days 1 and 7 post-injury, whereas ERK and SAPK/JNK activation was increased by burn injury only on day 1. Using the specific p38 inhibitor (SB203580), we confirmed that the increase in tumor necrosis factor α production by LPS-stimulated burn macrophages requires p38 activation. Although we demonstrated that injury increases macrophage TLR4 mRNA expression and intracellular expression of TLR4-myeloid differentiation protein-2 (MD-2) protein, macrophage cell-surface expression of TLR4-MD-2 was not changed by burn injury. Our results suggest that the injury-induced increase in TLR4 reactivity is mediated, at least in part, by enhanced activation of the p38 signaling pathway.
Systematic Review of Barriers to the Recruitment of Older Patients With Cancer Onto Clinical Trials
Authors: Townsley Carol A. , Selby Rita , Siu Lillian L.
Published: April 2005

Purpose

Older patients are significantly underrepresented in cancer clinical trials. A literature review was undertaken to identify the barriers that impede the accrual of this vulnerable population onto clinical trials and to determine what specific strategies are needed to improve the representation of older patients in research studies.

Methods

A systematic literature search was undertaken using several different strategies to identify relevant articles.

Results

Nine of 31 relevant papers from 159 citations were included. Age is a significant barrier to recruitment; only a quarter to one third of potentially eligible older patients are enrolled onto trials. Physicians' perceptions, protocol eligibility criteria with restrictions on comorbid conditions, and functional status to optimize treatment tolerability are the most important reasons resulting in the exclusion of older patients. Other barriers include the lack of social support and the need for extra time and resources to enroll these patients. Conversely, older patients do not view their age as an important reason for refusing trials.

Conclusion

Specific clinical trials confined to older patients should be conducted to evaluate tumor biology, treatment tolerability, and the effect of comorbid conditions. Protocol designs need to stratify for age and be less restrictive with respect to exclusions on functional status, comorbidity, and previous cancers, such that results are generalizable to older patients. Physician education to dispel unfounded perceptions, improved access to available clinical trials, and provision of personnel and resources to accommodate the unique requirements of an older population are possible solutions to remove the barriers of ageism.
TGFBR1☆6A May Contribute to Hereditary Colorectal Cancer
Authors: Bian Yansong , Caldes Trinidad , Wijnen Juul , Franken Patrick , Vasen Hans , Kaklamani Virginia , Nafa Khédoudja , Peterlongo Paolo , Ellis Nathan , Baron John A. , Burn John , Moeslein Gabriela , Morrison Patrick J. , Chen Yu , Ahsan Habibul , Watson Patrice , Lynch Henry T. , de la Chapelle Albert , Fodde Riccardo , Pasche Boris
Published: April 2005

Purpose

TGFBR1☆6A is a tumor susceptibility gene that increases breast, colon, and ovarian cancer risk. Fourteen percent of the general population carries TGFBR1☆6A, and TGFBR1☆6A homozygotes have a greater than 100% increased colon cancer risk compared with noncarriers. Low-penetrance genes such as TGFBR1☆6A may account for a sizable proportion of familial colorectal cancer occurrences. To test this hypothesis, we determined whether TGFBR1☆6A contributes to a proportion of mismatch repair (MMR) gene mutation–negative hereditary nonpolyposis colorectal cancer (HNPCC) patients.

Patients and Methods

A case-case study was performed of 208 index patients with HNPCC meeting the Amsterdam criteria. Patients were examined for mutations and genomic rearrangements in the MLH1, MSH2, and MSH6 genes and genotyped for TGFBR1☆6A. Tumor microsatellite instability status was available for 95 patients.

Results

A total of 144 patients (69.2%) carried a deleterious mutation and were classified as positive for MMR gene mutation; 64 patients (30.8%) had no evidence of mutations and were classified as MMR negative. TGFBR1☆6A allelic frequency was significantly higher among MMR-negative patients (0.195) than among MMR-positive patients (0.104; P = .011). The proportion of TGFBR1☆6A homozygotes was nine-fold higher among MMR-negative (6.3%) than among MMR-positive patients (0.7%; P = .032). The highest TGFBR1☆6A allelic frequency was found among MMR-negative patients with tumors exhibiting no microsatellite instability (0.211), and the lowest frequency was found among MMR-positive patients with tumors exhibiting microsatellite instability (0.121); the difference was not statistically significant (P = .17).

Conclusion

TGFBR1☆6A may be causally responsible for a proportion of HNPCC occurrences.
Expression ofInterleukin-10Splicing Variants Is a Positive Prognostic Feature in Relapsed Childhood Acute Lymphoblastic Leukemia
Authors: Wu Shuling , Geβner Reinhard , Taube Tillmann , von Stackelberg Arend , Henze Günter , Seeger Karl
Published: April 2005

Purpose

Biologic features of hematologic malignancies have prognostic implications and are essential elements in the design of current therapeutic trials. This study aimed to determine the expression of a splicing-derived variant of interleukin (IL) -10 in leukemic cells and its clinical relevance in children with acute lymphoblastic leukemia (ALL) at first relapse.

Patients and Methods

Between January 1997 and December 2001, bone marrow (BM) samples were collected from 98 children with first relapse of ALL at diagnosis. These patients were enrolled in the relapse trial ALL-REZ BFM (ALL-Relapse Berlin-Frankfurt-Münster) 95 and 96. The detection of IL-10 isoforms in leukemic cells of BM samples were performed by conventional reverse transcriptase polymerase chain reaction and by immunoblotting.

Results

IL-10 was detected in 93.9% BM samples. In addition to expressing full-length IL-10, a new splicing-derived IL-10 variant (termed IL-10δ3) that lacked the entire exon 3 was identified in leukemic cells. The IL-10δ3 variant was found in 80.4% of BM samples. Most importantly, expression of IL-10δ3 was associated with a significantly better response to chemotherapy (P = .001) and probability of event-free survival (P = .01) at 5 years.

Conclusion

These results indicate that splicing-derived IL-10 isoforms may modulate IL-10–mediated biologic effects and therapeutic efficacy in lymphatic disease, and expression of IL-10δ3 is a positive prognostic feature in relapsed childhood ALL.
Results of the Dutch National Study of the Palliative Effect of Irradiation Using Two Different Treatment Schemes for Non–Small-Cell Lung Cancer
Authors: Kramer Gijsbert W.P.M. , Wanders Stofferinus L. , Noordijk Ed M. , Vonk Ernest J.A. , van Houwelingen Hans C. , van den Hout Wilbert B. , Geskus Ronald B. , Scholten Mirjam , Leer Jan-Willem H.
Published: April 2005

Purpose

A national multicenter randomized study compared the efficacy of 2 × 8 Gy versus our standard 10 × 3 Gy in patients with inoperable stage IIIA/B (with an Eastern Cooperative Oncology Group score of 3 to 4 and/or substantial weight loss) and stage IV non–small-cell lung cancer.

Patients and Methods

Between January 1999 and June 2002, 297 patients were eligible and randomized to receive either 10 × 3 Gy or 2 × 8 Gy by external-beam irradiation. The primary end point was a patient-assessed score of treatment effect on seven thoracic symptoms using an adapted Rotterdam Symptom Checklist. Study sample size was determined based on an average total symptom score difference of more than one point over the initial 39 weeks post-treatment. The time course of symptom scores were also evaluated, and other secondary end points were toxicity and survival.

Results

Both treatment arms were equally effective, as the average total symptom score over the initial 39 weeks did not differ. However, the pattern in time of these scores differed significantly (P < .001). Palliation in the 10 × 3-Gy arm was more prolonged (until week 22) with less worsening symptoms than in 2 × 8-Gy. Survival in the 10 × 3-Gy arm was significantly (P = .03) better than in the 2 × 8-Gy arm with 1-year survival of 19.6% (95%CI, 14.1% to 27.3%) v 10.9% (95%CI, 6.9% to 17.3%).

Conclusion

The 10 × 3-Gy radiotherapy schedule is preferred over the 2 × 8-Gy schedule for palliative treatment, as it improves survival and results in a longer duration of the palliative response.
Patterns and Correlates of Local Therapy for Women With Ductal Carcinoma-In-Situ
Authors: Katz Steven J. , Lantz Paula M. , Janz Nancy K. , Fagerlin Angela , Schwartz Kendra , Liu Lihua , Deapen Dennis , Salem Barbara , Lakhani Indu , Morrow Monica
Published: April 2005

Purpose

Concerns have been raised about the quality of treatment for women with ductal carcinoma-in-situ (DCIS) because persistent high rates of mastectomy suggest overtreatment, whereas lower than expected rates of radiation therapy after breast-conserving surgery (BCS) suggest undertreatment.

Patients and Methods

All women with DCIS diagnosed in 2002 and who reported to the Detroit and Los Angeles Surveillance, Epidemiology, and End Results (SEER) registries were identified and surveyed shortly after receipt of surgery (response rate, 79.7%; n = 817). Analyses were restricted to patients with DCIS (n = 659) indicated by SEER stage data.

Results

Only 14.0% of patients at lowest risk of recurrence (based on tumor size and histologic grade) received a mastectomy compared with 22.8% and 52.6% of patients at intermediate and highest risk (P < .001). Only 13.1% of patients who were not influenced or slightly influenced by concerns about recurrence received mastectomy compared with 48.8% of women who were greatly influenced by this concern (P < .001). A between-geographic site difference in receipt of radiation after BCS was observed for the lowest risk group (38.9% in Los Angeles v 70.5% in Detroit) but not for the highest risk group (80.2% in Los Angeles v 85.9% in Detroit, P = .006 for site and risk group differences). Between-site differences in receipt of radiation after BCS were consistent with patient recall of surgeon discussions about treatment.

Conclusion

Surgeons are tailoring their recommendations for local therapy options for DCIS based on important clinical factors. Patient attitudes also play an important role in treatment decisions. The substantial influence of both surgeon opinion and patient attitudes should temper concerns about the quality of treatment for women with DCIS.
Randomized Trial of Hyperthermia and Radiation for Superficial Tumors
Authors: Jones Ellen L. , Oleson James R. , Prosnitz Leonard R. , Samulski Thaddeus V. , Vujaskovic Zeljko , Yu Daohai , Sanders Linda L. , Dewhirst Mark W.
Published: April 2005

Purpose

Randomized clinical trials have demonstrated hyperthermia (HT) enhances radiation response. These trials, however, generally lacked rigorous thermal dose prescription and administration. We report the final results of a prospective randomized trial of superficial tumors (≤ 3 cm depth) comparing radiotherapy versus HT combined with radiotherapy, using the parameter describing the number of cumulative equivalent minutes at 43°C exceeded by 90% of monitored points within the tumor (CEM 43°C T90) as a measure of thermal dose.

Methods

This trial was designed to test whether a thermal dose of more than 10 CEM 43°C T90 results in improved complete response and duration of local control compared with a thermal dose of ≤ 1 CEM 43°C T90. Patients received a test dose of HT ≤ 1 CEM 43°C T90 and tumors deemed heatable were randomly assigned to additional HT versus no additional HT. HT was given using microwave spiral strip applicators operating at 433 MHz.

Results

One hundred twenty-two patients were enrolled; 109 (89%) were deemed heatable and were randomly assigned. The complete response rate was 66.1% in the HT arm and 42.3% in the no-HT arm. The odds ratio for complete response was 2.7 (95% CI, 1.2 to 5.8; P = .02). Previously irradiated patients had the greatest incremental gain in complete response: 23.5% in the no-HT arm versus 68.2% in the HT arm. No overall survival benefit was seen.

Conclusion

Adjuvant hyperthermia with a thermal dose more than 10 CEM 43°C T90 confers a significant local control benefit in patients with superficial tumors receiving radiation therapy.
Capecitabine As First-Line Treatment for Patients Older Than 70 Years With Metastatic Colorectal Cancer: An Oncopaz Cooperative Group Study
Authors: Feliu Jaime , Escudero Pilar , Llosa Ferrán , Bolaños Matilde , Vicent Jose-Manuel , Yubero Alfonso , Sanz-Lacalle Jose-Javier , Lopez Rafael , Lopez-Gómez Luis , Casado Enrique , Gómez-Reina María-José , González-Baron Manuel
Published: April 2005

Purpose

To determine the tolerability of capecitabine in elderly patients with advanced colorectal cancer (CRC).

Patients and Methods

Fifty-one patients with advanced CRC who were ≥ 70 years and considered ineligible for combination chemotherapy received oral capecitabine 1,250 mg/m2 twice daily on days 1 to 14 every 3 weeks. Patients with a creatinine clearance of 30 to 50 mL/min received a dose of 950 mg/m2 twice daily.

Results

A total of 248 cycles of capecitabine were administered (median, five cycles; range, one to eight cycles). The overall response rate was 24% (95% CI, 15% to 41%), including two complete responses (CR; 4%) and 10 partial responses (PR; 20%). Disease control (CR + PR + stable disease) was achieved in 67% of patients. The median times to disease progression and overall survival were 7 months (95% CI, 6.4 to 9.5 months) and 11 months (95% CI, 8.6 to 13.3 months), respectively. Of the 35 patients evaluated for clinical benefit response, 14 (40%; 95% CI, 24% to 58%) showed clinical benefit. Capecitabine was well tolerated. Treatment-related grade 3 and 4 adverse events were observed in only six patients (12%), and the most common events were diarrhea, hand-foot syndrome, and thrombocytopenia. One patient (2%) had an episode of angina, but no treatment-related deaths were reported.

Conclusion

Our findings suggest that capecitabine is effective and well tolerated in elderly patients with advanced CRC who are considered ineligible for combination chemotherapy.