bluuebunny/crossref_metadata_2025 huggingface dataset:
InVivo Detection of Intracellular Signaling Pathwaysin Developing Thymocytes
Authors: Michie Alison M. , Zúñiga-Pflücker Juan Carlos
Published: June 2008

Information regarding the intracellular signaling processes that occur during the development
of T cells has largely been obtained with the use of transgenic mouse models, which although
providing invaluable information are time consuming and costly. To this end, we have developed
a novel system that facilitates the InVivo analysis of signal transduction pathways during
T‐lymphocyte development. This approach uses reporter‐plasmids for the detection of
intracellular signals mediated by the mitogen‐activated protein kinase or cyclic AMP‐dependent
protein kinase. Reporter‐plasmids are transfected into thymocytes in fetal thymic organ
culture by accelerated DNA/particle bombardment (gene gun), and the activation of a signaling
pathway is determined in the form of a standard luciferase assay. Importantly, this powerful
technique preserves the structural integrity of the thymus, and will provide an invaluable
tool to study how thymocytes respond to normal environmental stimuli encountered during
differentiation within the thymic milieu. Thus, this method allows for the monitoring of signals
that occur in a biological time frame, such as during differentiation, and within the natural
environment of differentiating cells.
Gender‐Related Differences in the Rates of Age AssociatedThymic Atrophy
Authors: Aspinall Richard , Andrew Deborah
Published: June 2008

Age associated thymic atrophy has been shown to be linked to problems with rearrangement
of the β chain of the T cell receptor (TCR) in male mice during the early phases of the intrathymic
T cell developmental pathway. In this study, thymic atrophy in female mice was found
to occur at a different rate than in male mice. At 9 months of age there was a significantly
greater number of cells in the thymus of female mice compared with male mice, with the
major difference found in the CD4+CD8+ populations. The thymii of female mice at 9 months
of age contained double the number of these cells compared with male mice. Analysis of the
CD4+CD8+ cells at 9 months of age demonstrated increased numbers of cells expressing
higher levels of CD3 in females compared with males indicating that in females more of these
cells were producing successful αβTCR pairings. In F5 transgenic mice comparison of the
CD4+CD8+ population revealed no significant difference in their absolute numbers at
9 months of age. These results indicate that the gender differences at this time point were due
to fewer permitted divisions prior to the expression of a selectable TCR α chain within the
CD4+CD8+ populations in male compared with female mice. This gender difference was not
due to the action of testosterone and unlikely to be due to differences in the level of oestrogen.
The potential mechanisms of this difference may be related to a regulatory feedback of
peripheral T cells on the developing thymocyte populations. Such age related changes in the
numbers of cells within distinct thymic subpopulations leads to the possibility that the potential
repertoire in females is greater than in males later in life.
GaAs Triac‐like Triangular Barrier Switch Prepared by Molecular Beam Epitaxy
Authors: Lef M. R. , Yarn K. F. , Chen C. C. , Chang W. R.
Published: June 2008

A new S‐shaped negative differential resistance (NDR) switching device, prepared by
molecular beam epitaxy (MBE), has been successfully developed in a GaAs double
triangular barrier structure. Symmetrical bidirectional S‐shaped NDR characteristics are
observed experimentally. The bidirectional current‐voltage (I–V) characteristics exhibit
a new type of NDR caused by an avalanche multiplication process in reverse biased
base‐collector region and barrier redistribution. Under a base current injection with
respect to the cathode, the device exhibits a conventional transistor with a current gain
of 1.2 at room temperature. The experimentally electrical results can be easily understood
by an equivalent circuit. In addition, a new optoelectronic switching device is also
proposed which may have the potential for bidirectional wave length emission.
Lack of Apoptosis of Infiltrating Cells as the Mechanismof High Susceptibility to EAE in DA Rats
Authors: Lukic Miodrag L. , Mensah-Brown Eric , Galadari Sehamuddin , Shahin Allen
Published: June 2008

Dark Agouti (DA) rats are highly susceptible to induction of Th‐l‐mediated autoimmunity
disease, including experimental allergic encephalomyelitis (EAE). In contrast to other susceptible
rat strains in which disease is induced only with encephalitogen emulsified in complete
Freund′s adjuvants (CFA), in DA rats EAE develops after injection of encephalitogen in
incomplete Freund′s adjuvants (IFA) or Titermax, putative Th‐2 directed adjuvant. Lymph
node cells derived from immunized DA rats and stimulated invitro produce significantly
more Interferon‐γ (IFN‐γ) than resistant Albino Oxford (AO) rats. However, cells derived
from both strains produce large amounts of IL‐10 but not IL‐4. Immunized lymph node cells
derived from EAE susceptible (AO × DA) F1rats induce clinical signs of disease in sublethally
irradiated parental DA but not AO rats. The pathohistology of the target tissue in these
recipients clearly demonstrated infiltration of mononuclear cells in both parental strains.
However, the number of CD4+ cells was significantly higher and number of apoptotic cells
significantly lower in DA rats sacrificed 8 days after passive transfer. We postulate that in
addition to higher IFN‐γ and TNF‐α production, resistance to early apoptosis of the invading
cells in the target tissue possibly due to lack of downregulation by TGF‐β leads to exceptional
susceptibility to EAE in DA rats.
Pentoxifylline Prevents Autoimmune MediatedInflammation in Low Dose Streptozotocin InducedDiabetes
Authors: Stošić-Grujičić Stanislava D. , Maksimović Danijela D. , Stojković Marija B. Mostarica , Lukić Miodrag L.
Published: June 2008

Xanthine derivative, pentoxifylline (PTX), has been recently shown to exert a protective effects
in certain animal models of autoimmunity, including diabetes in NOD mice. In the present
study, the immunomodulatory potential of PTX was investigated in autoimmune diabetes
induced by multiple low doses of streptozotocin (MLD‐SZ) in genetically susceptible CBA/H
mice (tested with 40 mg SZ/kg b.w. for 5 days) and DA rats (tested with 20 mg/kg b.w. for 5
days). In both species, 2 – 3 weeks following the MLD‐SZ treatment, sustained hyperglycemia
developed, as an outcome of inflammatory reaction with endothelial cell activation and accumulation
of mononuclear cells. Although there was no evidence of typical insulitis in early disease
development (day 10), in both rats and mice, macrophages, CD4+ and CD8+ cells were present in the islets of Langerhans as diffuse mononuclear infiltrates with the expression of
IFN‐γ and inducible NO synthase (iNOS). Administration of PTX (200 mg/kg/day for 10 days)
in combination with MLD‐SZ reduced insulitis and the production of mediators tested, and prevented
the development of hyperglycemia. These results suggest that beneficial effects of PTX
involve down‐regulation of local proinflammatory cytokine‐mediated NO synthase pathway.
They also demonstrate that in addition to ameliorating spontaneous autoimmunity in NOD
mice, PTX may be effective in downregulating an inflammatory autoimmune process triggered
in susceptible host by an external agents, such as streptozotocin.
Dependence on the Partial Pressure of Oxygen on the Shift in the Energy Band‐gap of CdOThin Films in the Visible Region
Authors: Grado-Caffaro M. A. , Grado-Caffaro M. , Sapienza S. L.
Published: June 2008

In this paper, the dependence on the partial pressure of oxygen of the shift in the energy
band‐gap of CdO thin films for the visible region is investigated from the theoretical
point of view on an experimental basis. In our analysis, the role played by the dependence
of the carrier density upon the above pressure is emphasized.
Human FDC express PrPc invivo and invitro
Authors: Thielen Caroline , Antoine Nadine , Mélot France , Cesbron Jean-Yves , Heinen Ernst , Tsunoda Rikiya
Published: June 2008

Prion diseases are fatal neurodegenerative disorders caused by accumulation of abnormal
prion protein (protease‐resistant prion, PrPres). PrPres accumulation is also detected in lymphoid
organs after peripheral infection. Several studies suggest that follicular dendritic cells
(FDC) could be the site of PrPres retention and amplification.

Here we show that human follicular dendritic cells can express normal cellular prion protein
(PrPc) both insitu and invitro. When tonsillar cryosections were treated with anti‐PrP
antibody, the label was found on some very delicate cell extensions inside the lymphoid follicles,
especially in the germinal centres. These extensions react with DRC1 antibody, used frequently
to label FDC. Other structures labelled with anti‐PrP antibody were the keratinocytes.

To confirm the ability of FDC to synthesise PrPc, we isolated FDC by a non‐enzymatic
procedure and cultured them. By cytochemistry and flow cytometry it was clearly shown that
FDC do produce PrPc.
Thermal Effect and Frequency Response Analyses on Heterojunction Bipolar Power Transistor
Authors: Yarn K. F. , Ho K. H.
Published: June 2008

Heterojunction bipolar transistors (HBT) based on Npn AlGaAs/GaAs material system
have attracted considerable attention for microwave power and digital applications due
to their high speed and high current capabilities. In this paper, a numerical model based
on the Npn AlGaAs/GaAs HBT structure for the carrier transport is presented. Three
figures of merit on device operation, current gain, cut‐off frequency and maximum
oscillation frequency are calculated. Besides, thermal instability plays an important
role on power HBT resulted from the low thermal conductivity in GaAs. The
generated heat will increase the junction temperature and cause self‐destruction.
Therefore, the thermal runaway study of the junction temperature, current–voltage
(IV) characteristics and frequency response using an analytical thermal model is
described.
Enforced Expression of Bcl‐2 Selectively Perturbs Negative Selection of Dual Reactive Antibodies
Authors: Notidis Evangelia , Hande Shailaja , Manser Tim
Published: June 2008

We investigated the role of apoptosis in the development of B cell memory by analyzing the
(p‐azophenylarsonate) Ars response in a line of A strain mice in which expression of human
Bcl‐2 was enforced in the B cell compartment. Previous studies of the Ars immune response in
these A. Bcl‐2 mice, demonstrated that a large percentage of the antibodies expressed by the Ars
induced memory B cell compartment had accumulated point mutations via somatic hypermutation
that increased their affinity for both Ars and the autoantigen DNA (“dual reactive” antibodies).
This was in sharp contrast to normal A strain mice which displayed no dual reactive B cells
in their Ars induced memory B cell compartment. These data suggested that interference with
apoptotic pathways regulated by Bcl‐2 allows developing memory B cells that have acquired
autoreactivity to bypass a peripheral tolerance checkpoint. Further studies of these mice,
reported here, demonstrate that enforced expression of Bcl‐2 does not alter serum antibody
affinity maturation nor positive selection of B cells expressing somatically mutated antibody
with an increased affinity for Ars. Moreover, the somatic hypermutation process was unaffected
in A. Bcl‐2 mice. Thus, enforced expression of Bcl‐2 in A. Bcl‐2 mice appears to selectively
alter a negative selection process that operates during memory B cell differentiation.
Some Considerations on Electronic Energy of Itinerant‐electron Metamagnetic Materialswith Volume‐dependent Exchange Energy
Authors: Grado-Caffaro M. A. , Grado-Caffaro M. , Sapienza S. L.
Published: June 2008

Electronic energy of itinerant‐electron metamagnetic materials is examined by taking
into consideration volume‐dependent exchange energy between up and down spin electrons.
In particular, the average value of the electronic energy is formulated in terms of
the energy bandwidth which is closely related to volume; from the above average value,
the average value of the exchange energy may be evaluated.
T Cell Mediated Antibody lnvariance in an Immune Response Against A Bacterial Carbohydrate Antigen Requires CD28/B7–1 Costimulation
Authors: Rademaekers André , Kölsch Eckehart , Specht Christoph
Published: June 2008

The humoral immune response against α(1 → 3) dextran (Dex) in BALB/c mice is characterized
by the formation of predominantly IgM antibodies bearing the J558 idiotype. IgG antibodies
do not appear in euthymic mice. In athymic animals however, the response proceeds to
a vigorous IgG production. In euthymic mice formation of IgG is suppressed by J558 idiotype‐
specific regulatory T cells recognizing in association with I‐Ed and in cognate T/B interaction
the VH CDR3 derived peptide of the J558 idiotpye. Only B‐2 lymphocytes produce
IgG whereas B‐1 cells do not participate in the production of this Ig class. Using a novel synthetic
all α(1 → 3)‐D‐gluco configurated tetrasaccharide the Dex‐specific B cells can for the
first time be analyzed in FACS. In experiments using this newly designed low molecular Dex
no signs of B cell apoptosis can be found. This demonstrates a true silencing of persisting Bγ
memory cells and supports previous by adoptive transfer experiments. In this suppression an
involvement of CD28/B7–1 interaction can be demonstrated which is a necessary costimulatory
suppression signal in addition to the cognate TCR/peptide‐I‐Ed interaction between J558
Id‐specific T cells and J558 idiotype beating B cells. This results in an activation of 178–4 Ts
cells, leading to an overall suppression of the Dex‐specific IgG isotype production on the one
hand and on the other hand provides a signal for the survival and clonal expansion of J558
Id‐positive B cells.
Multiple Interactions between Peroxisome Proliferators‐Activated Receptors and the Ubiquitin‐Proteasome System and Implications for Cancer Pathogenesis
Authors: Genini Davide , Carbone Giuseppina M. , Catapano Carlo V.
Published: June 2008

The peroxisome proliferator‐activated receptors (PPAR) α,  β/δ, and γ are ligand‐activated nuclear receptors involved in a number of physiological processes, including lipid and glucose homeostasis, inflammation, cell growth, differentiation, and death. PPAR agonists are used in the treatment of human diseases, like type 2 diabetes and dyslipidemia, and PPARs appear as promising therapeutic targets in other conditions, including cancer. A better understanding of the functions and regulation of PPARs in normal and pathological processes is of primary importance to devise appropriate therapeutic strategies. The ubiquitin‐proteasome system (UPS) plays an important role in controlling level and activity of many nuclear receptors and transcription factors. PPARs are subjected to UPS‐dependent regulation. Interestingly, the three PPAR isotypes are differentially regulated by the UPS in response to ligand‐dependent activation, a phenomenon that may be intrinsically connected to their distinct cellular functions and behaviors. In addition to their effects ongene expression, PPARs appear to affect protein levels and downstream pathways also by modulating the activity of the UPS in target‐specific manners. Here we review the current knowledge of the interactions between the UPS and PPARs in light of the potential implications for their effects on cell fate and tumorigenesis.
Using Signal Envelope Detection for Online and Offline RF MEMS Switch Testing
Authors: Simeu E. , Nguyen H. N. , Cauvet P. , Mir S. , Rufer L. , Khereddine R.
Published: June 2008

The test of radiofrequency (RF) integrated circuits at their ever‐increasing operating frequency range requires sophisticated test equipment and is time‐consuming and, therefore, very expensive. This paper introduces a new method combining low‐frequency actuation signal as test stimuli and signal envelope detection applied on the RF output signal in order to provide a low‐cost mean for production testing of RF MEMS switches embedded in system‐in‐package (SiP) devices. The proposed approach uses the principle of alternate test that replaces conventional specification‐based testing procedures. The basic idea is to extract the high‐frequency characteristics of the switch from the signal envelope of the response. Output parameters like “on” and “off” transition time are extracted at low frequency and used in a regression process to predict RF conventional specifications like S‐parameters. The paper also provides a set of recursive estimation algorithms suitable for online testing. In this context, “on” and “off” transition time estimated from the output low‐frequency envelope is used as test metrics and is concurrently updated using recursive algorithms. Validation results obtained on a capacitive RF switch model are presented.
Nonlinear Modeling of Cables with Flexural Stiffness
Authors: Lacarbonara Walter , Pacitti Arnaud
Published: June 2008

A geometrically exact formulation of cables suffering axis stretching and flexural curvature is
presented. The dynamical formulation is based on nonlinearly viscoelastic constitutive laws
for the tension and bending moment with the additional constitutive nonlinearity accounting
for the no‐compression condition. A continuation method, combined with a mixed finite‐difference
spatial discretization, is then employed to path‐follow the static responses of cables subject to
forces or support displacements. These computations, conducted in the quasistatic regime, are
based on cables with linearly elastic material behaviors, whereas the nonlinearity is in the geometric
stiffness terms and the no‐compression behavior. The finite‐difference results have been
confirmed employing a weak formulation based on quadratic Lagrangian finite elements.
The influence of the flexural stiffness on the nonlinear static responses is assessed comparing the
results with those obtained for purely extensible cables. The properties of the frequencies of the
linear normal modes of cables with flexural stiffness are also investigated and compared with those
of purely extensible cables.
Silicon Photonic Biosensors for Lab‐on‐a‐Chip Applications
Authors: Zinoviev Kirill , Carrascosa Laura G. , Sánchez del Río José , Sepúlveda Borja , Domínguez Carlos , Lechuga Laura M.
Published: June 2008

In the last two decades, we have witnessed a remarkable progress in the development of biosensor devices and their application in areas such as environmental monitoring, biotechnology, medical diagnostics, drug screening, food safety, and security, among others. The technology of optical biosensors has reached a high degree of maturity and several commercial products are on the market. But problems of stability, sensitivity, and size have prevented the general use of optical biosensors for real field applications. Integrated photonic biosensors based on silicon technology could solve such drawbacks, offering early diagnostic tools with better sensitivity, specificity, and reliability, which could improve the effectiveness of in‐vivo and in‐vitro diagnostics. Our last developments in silicon photonic biosensors will be showed, mainly related to the development of portable and highly sensitive integrated photonic sensing platforms.
Antidepressant Interactions with the NMDA NR1-1b Subunit
Authors: Raabe Richard , Gentile Lisa
Published: June 2008

The targets for tricyclic antidepressants (TCAs), selective serotonin reuptake inhibitors (SSRIs), and selective norepinephrine reuptake inhibitors (SNRIs) are known to be the serotonin and norepinephrine transport (reuptake) proteins which are embedded in presynaptic nerve terminals and function to bring these neurotransmitters from the synaptic cleft back into the presynaptic neuron. Using a combination of intrinsic and extrinsic fluorescence quenching, Stern-Volmer analysis, and protease protection assays, we have shown that therapeutics from each of these three classes of antidepressants bind to the extracellular S1S2 domain of the NR1-1b subunit of the NMDA receptor. These results are in agreement with recent work from our lab demonstrating the interaction of antidepressants with the S1S2 domain of the GluR2 subunit of the AMPA receptor, another member of the ionotropic glutamate receptor subfamily, as well as work from other labs, and continue the discussion of the involvement of ionotropic glutamate receptors in depression.
Endoscopic Treatment of Vesicoureteral Reflux with Dextranomer/Hyaluronic Acid in Children
Authors: Cerwinka Wolfgang H. , Scherz Hal C. , Kirsch Andrew J.
Published: June 2008

Purpose. The goal of this review is to present current indications, injectable agents, techniques, success rates, complications, and potential future applications of endoscopic treatment for vesicoureteral reflux (VUR) in children.Materials and Methods. The endoscopic method currently achieving one of the highest success rates is the double hydrodistention-implantation technique (HIT). This method employs dextranomer/hyaluronic acid copolymer, which has been used in pediatric urology for over 10 years and may be at present the first choice injectable agent due to its safety and efficacy.Results. While most contemporary series report cure rates of greater than 85% for primary VUR, success rates of complicated cases of VUR may be, depending on the case, significantly lower. Endoscopic treatment offers major advantages to patients while avoiding potentially complicated open surgery. As the HIT method continues to be applied to complex cases of VUR and more outcome data become available, the indication for endoscopic treatment may exceed the scope of primary VUR.Conclusions. Endoscopic injection is emerging as the treatment of choice for VUR in children.
Discrete Vector Models for Catalysis and Autocatalysis
Authors: Haß Ernst-Christoph , Sauerbrei Sonja , Jörg Plath Peter
Published: June 2008

Based on Ruch′s concept of diagram lattices formed by Young
diagrams we investigated the possibility to transform incomparable
diagrams into comparable ones by means of vector catalysis. Ruch′s
diagram lattices allow a very general description of comparing
frequency distributions by their mixing‐character as an order
relation which is equivalent to majorisation in the mathematical
theory of inequalities. Dealing with Young diagrams or vectors
containing only integer components, respectively, vector catalysis
is strongly related to entanglement catalysis in quantum
informatics. In a very systematic way the diagram lattices of the
partitions up to the number n = 20 have been searched for
incomparable pairs which can be catalysed. This concept opens the
opportunity for regarding vector catalysis as a universal
phenomenon which is not restricted to the quantum mechanical idea
of entanglement catalysis. Such a general approach offers the possibility to compare vector
catalysis with chemical ideas of catalysis and autocatalysis in a
very fundamental sense. We emphasize that
vector catalysis is a universally valid procedure for
classification purposes, where incomparable sequences of symbols
are transformed into comparable ones in a much higher dimensional
space ignoring any physical interpretation of these symbols.
Achieving High Aspect Ratio of Track Length to Width in Molds for Discrete Track Recording Media
Authors: Aung K. O. , Shankaran C. , Sbiaa R. , Tan E. L. , Wong S. K. , Piramanayagam S. N.
Published: June 2008

Discrete track media (DTM) fabricated by nanoimprint lithography (NIL) is considered as a potential technology for future hard disk drives (HDD). In the fabrication of a master mold for NIL, patterning the resist tracks with a narrow distribution in the width is the first critical step. This paper reports the challenges involved in the fabrication of high aspect ratio discrete tracks on Polymethylmethacrylate (PMMA) resist by means of electron beam lithography. It was observed that fabrication parameters applied for successful patterning of discrete tracks in nanoscale length were not directly suitable for the patterning of discrete tracks in micron scale. Hence different approaches such as thick layer resist coating, introducing of post exposure baking process, and varying of exposure parameters were used in order to achieve uniform sharp discrete tracks in micron scale length on the resist. The optimal parameters were used to pattern 20 μm long tracks with 70 nm track pitch on the resist.
Interactions of Constipation, Dysfunctional Elimination Syndrome, and Vesicoureteral Reflux
Authors: Halachmi Sarel , Farhat Walid A.
Published: June 2008

Vesicoureteral reflux (VUR) is simply described as incompetence of the unidirectional valve at the ureterovesical junction (UVJ), leading to backflow of urine to the kidney. Today, it is clear that VUR is not only related to the UVJ function but also to a combination of processes including immunity, bladder and pelvic floor function, dysfunctional voiding, and constipation. Although our surgical aims directed towards improving the valve coaptation at the UVJ, we understand today the importance of the diagnosis and treatment of constipation and dysfunctional voiding adjunctively.
Differential Subordinations Associated with Multiplier Transformations
Authors: Cătaş Adriana , Oros Georgia Irina , Oros Gheorghe
Published: June 2008

The authors introduce new classes of analytic
functions in the open unit disc which are defined by using multiplier transformations.
The properties of these classes will be studied by using techniques involving
the Briot‐Bouquet differential subordinations. Also an integral transform is established.
Protein Coding Gene Nucleotide Substitution Pattern in the Apicomplexan ProtozoaCryptosporidium parvumandCryptosporidium hominis
Authors: Ge Guangtao , Cowen Lenore , Feng Xiaochuan , Widmer Giovanni
Published: June 2008

Cryptosporidium parvumandC. hominisare related protozoan pathogens which infect the intestinal epithelium of humans and other vertebrates. To explore the evolution of these parasites, and identify genes under positive selection, we performed a pairwise whole-genome comparison between all orthologous protein coding genes inC. parvumandC. hominis. Genome-wide calculation of the ratio of nonsynonymous versus synonymous nucleotide substitutions (dN/dS) was performed to detect the impact of positive and purifying selection. Of 2465 pairs of orthologous genes, a total of 27 (1.1%) showed a high ratio of nonsynonymous substitutions, consistent with positive selection. A majority of these genes were annotated as hypothetical proteins. In addition, proteins with transmembrane and signal peptide domains are significantly more frequent in the highdN/dSgroup.
Experimental Investigation of the Transition to Spatiotemporal Chaos with a System‐Size Control Parameter
Authors: Spiegel Daniel R. , Johnson Elliot R.
Published: June 2008

Using a localized laser‐heating method to allow the use of system size as a control parameter, we experimentally investigate, using liquid‐crystal electroconvection with soft boundary conditions, the onset of spatial temporal chaos (STC) with increasing system size. We find that temporal periodicity is significantly quenched as the system size increases. The increase of the fourth moment (kurtosis) of the temporal Fourier transform provides a very useful quantitative measure of the loss of temporal periodicity (hence the onset of STC) as the pattern size increases, and also provides a simple means for determining a natural chaotic length scale. This length scale is comparable to the length of vertical rows observed in the original pattern. Our experiments, thus, imply that there are well‐defined building blocks, which in our case are easily visualized, that control the dynamics in STC liquid crystal convection. The results of our experiments appear to be consistent with the conclusions of recent STC computer simulations carried out by Fishman and Egolf.
New Diagnostic Method for Liver Fibrosis and Cirrhosis
Authors: Han Kwang-Hyub , Yoon Ki Tae
Published: June 2008

Liver fibrosis, i.e. excessive accumulation of extracellular matrix proteins, occurs in most types of chronic liver diseases. The prognosis and management of chronic liver diseases depend on the degree of liver fibrosis. Therefore, the assessment of liver fibrosis provides useful information not only for diagnosis but also for treatment planning. Although liver biopsy is still the gold standard for assessing hepatic fibrosis, it has some technical limitations and risks. Furthermore, the dynamic process of liver fibrosis resulting from progression and regression cannot be quantified by liver biopsy. Therefore, alternative, simple, reliable and noninvasive tests are needed to assess the stage of fibrosis. Several noninvasive direct and indirect serum markers able to predict the presence of significant fibrosis or cirrhosis in patients with chronic liver disease with considerable accuracy have been reported. However, since most of these markers require complicated calculations, clinical application is difficult. Transient elastography (FibroScan®) is a new method for the evaluation of liver stiffness. The technique is based on changes in tissue elasticity induced by hepatic fibrosis. Liver stiffness measured by transient elastography is a noninvasive, reproducible and reliable method to assess hepatic fibrosis as well as to diagnose liver cirrhosis. Based on accumulating clinical data, clinical applications of elastography will increase in the near future.
Recent Advances in Tumor Markers of Human Hepatocellular Carcinoma
Authors: Yoon Seung Kew
Published: June 2008

Hepatocellular carcinoma (HCC) is one of the most devastating malignancies in the world and is the third most common cause of cancer-related death in Korea. Because most HCC are accompanied by chronic liver disease that results from hepatitis B or C viruses, prognosis is still poor even after surgical resection of the tumor. Moreover, diagnosis of advanced HCC still leads to an extremely bleak prognosis. Earlier detection of HCC, therefore, could improve patient survival. Accordingly, the development of tumor markers that can detect HCC at even earlier stages is essential. The functions of tumor markers include prediction of prognosis or therapeutic response as well as diagnosis or screening of cancer. Possible candidate tumor markers may be quantitative alterations in DNA-, RNA- or protein-based molecules in tumorous conditions assessed by various technologies, e.g. serological assays, microarrays, mass spectrometry and proteomics. However, validation and clinical implementation is needed after the discovery of novel genes. An ideal tumor marker for HCC would be sensitive and specific enabling to differentiate it at an early stage from premalignant lesions like dysplastic nodules. In addition, the marker should be easily measurable, reproducible and minimally invasive. Although it is important to identify new biomarkers for HCC, the validation and cost-effectiveness of those markers as diagnostic or prognostic tools need confirmation in large-scale studies in clinical practice.
Hepatocellular Carcinoma in Patients Undergoing Living-Donor Liver Transplantation
Authors: Maetani Yoji S. , Ueda Mikiko , Haga Hironori , Isoda Hiroyoshi , Takada Yasutsugu , Arizono Shigeki , Hirokawa Yuusuke , Shimada Kootaro , Shibata Toshiya , Kaori Togashi
Published: June 2008

Objective: To compare 8-detector row helical computed tomography (CT) findings with histopathology in patients with hepatocellular carcinoma (HCC) who had undergone living-donor liver transplantation (LDLT). Materials and Methods: This institutional review board-approved prospective study was performed between February 12, 2003 and November 12, 2004; of the 78 candidates for LDLT due to HCC who underwent preoperative multidetector CT (MDCT), 48 transplant recipients met our criteria and in 41 of them, HCCs were diagnosed with <15 lesions on MDCT; these patients represented the study population. Results of preoperative CT were correlated with histopathological results after 5-mm sagittal slicing of the explanted liver. Following the injection of contrast medium (2 ml/kg body weight of 300 mg I/ml), triple-phase contrast-enhanced images were obtained. CT was performed using the following parameters: detector row configuration, 8 × 1 mm, reconstruction interval, 1 mm, 200 mA s and 120 kVp. Image analysis was performed in consensus by three abdominal radiologists using 1-mm-thick slices with 0.5-mm overlap with paging as well as multiplanar reformatting (MPR; i.e. axial, coronal and sagittal images). Results: A total of 134 HCCs were identified by pathological examination. The mean lesion size was 21 mm. Sensitivity, positive predictive value and accuracy for HCC detection were 87, 96 and 84% for all lesions, respectively, and 99, 100 and 97% for lesions >1 cm, respectively, but only 46, 76 and 41% for tumors <1 cm, respectively (n = 28). There were 12 false-negative lesions but only 5 false-positive findings. Conclusion: MDCT combined with the paging method and MPR images is very effective in the detection of HCCs >1 cm in diameter with a very low false-positive rate.
Diagnostic Accuracy of Multi-/Single-Detector Row CT and Contrast-Enhanced MRI in the Detection of Hepatocellular Carcinomas Meeting the Milan Criteria before Liver Transplantation
Authors: Kim Se Hyung , Choi Byung Ihn , Lee Jae Young , Kim Soo Jin , So Young Ho , Eun Hyo Won , Lee Jeong Min , Han Joon Koo
Published: June 2008

Liver transplantation has been considered to be the only causal treatment for liver cirrhosis patients with hepatocellular carcinoma (HCC) due to its theoretical advantage of eliminating both the tumor and liver disease. However, because of the shortage of donor organs, it is strongly recommended that liver transplantations should be performed on cirrhotic patients with HCCs only when the patients meet the predetermined criteria in terms of number and extent of HCCs. Imaging is thus decisive in the patient inclusion or exclusion from transplantation lists. The imaging techniques used are CT, MRI and ultrasonography. The latter has been proven to be ineffective for HCC surveillance in transplant recipients because of its heavy operator dependence and unreliable detection of small and intermediately sized HCCs. The purpose of this article, then, is to systematically review the diagnostic performances of single-/multidetector row CT, dynamic gadolinium-enhanced MRI, superparamagnetic iron oxide (SPIO)-enhanced MRI and double-contrast MRI using both gadolinium and SPIO for the detection of HCCs with special emphasis on liver transplantation.
Noninvasive Evaluation of Hepatic Fibrosis Using Serum Fibrotic Markers, Transient Elastography (FibroScan) and Real-Time Tissue Elastography
Authors: Tatsumi Chie , Kudo Masatoshi , Ueshima Kazuomi , Kitai Satoshi , Takahashi Shunsuke , Inoue Tatsuo , Minami Yasunori , Chung Hobyung , Maekawa Kiyoshi , Fujimoto Kenji , Akiko Tonomura , Takeshi Mitake
Published: June 2008

Objective: The aim of this study was to investigate the accuracy of noninvasive tests, e.g. serum fibrotic markers, transient elastography and real-time tissue elastography, in the diagnosis of hepatic fibrosis, and to determine whether they can replace liver biopsy. Methods: 119 patients with chronic liver disease were included in this study. Serum fibrotic markers including hyaluronic acid, type IV collagen, type IV collagen 7S domain and type III procollagen-N-peptide were measured. Aspartate aminotransferase (AST) and platelet counts were also measured to calculate the AST to platelet ratio index (APRI). Liver stiffness was measured using FibroScan and real-time tissue elastography. Results: The fibrotic stage, determined by histopathological diagnosis of a liver biopsy sample, did not correlate as well with serum fibrotic markers although it was useful to diagnose liver cirrhosis. However, the stage of hepatic fibrosis correlated well with liver stiffness measured by FibroScan. FibroScan was also a much better predictor of liver cirrhosis than APRI. Furthermore, the levels of liver strain measured by real-time tissue elastography correlated well with liver stiffness (p < 0.05). Conclusion: Serum fibrotic markers and FibroScan are useful for distinguishing liver cirrhosis (F4) from chronic hepatitis (F1–F3). In addition, real-time tissue elastography is a novel and promising method to determine the stage of hepatic fibrosis.
Cancer Stem Cells in Breast: Current Opinion and Future Challenges
Authors: Charafe-Jauffret Emmanuelle , Monville Florence , Ginestier Christophe , Dontu Gabriela , Birnbaum Daniel , Wicha Max S.
Published: June 2008

There is increasing evidence for the cancer stem cell hypothesis, which holds that cancers are driven by a cellular subcomponent that has stem cell properties, that is, self-renewal, tumorigenicity and multilineage differentiation capacity. The cancer stem cell hypothesis modifies our conceptual approach of oncogenesis and shall have implications in breast cancer prevention, detection and treatment, especially in metastatic breast cancer for which no curative treatment exists. Given the specific stem cell features, novel therapeutic pathways can be targeted. Following this approach, new molecules are currently in development. Focusing on the cross-talk between stem cells and their microenvironment is also a promising way to explore how to better target cancer stem cells and be curative.
The Molecular Pathology of Hereditary Breast Cancer
Authors: Palacios J. , Robles Frías M.J. , Castilla M.A. , López-García M.A. , Benítez J.
Published: June 2008

Hereditary breast cancer arising in carriers of mutations in the BRCA1 and BRCA2 genes differs from sporadic breast cancer and from non-BRCA1/2 familial breast carcinomas. Most BRCA1 carcinomas have the basal-like phenotype and are high-grade, highly proliferating, estrogen receptor-negative and HER2-negative breast carcinomas, characterized by the expression of basal markers such as basal keratins, P-cadherin and epidermal growth factor receptor. BRCA1 carcinomas frequently carry p53 mutations. The basal-like phenotype is only occasionally found in BRCA2 carcinomas, which tend to be estrogen and progesterone receptor positive. BRCA1 and BRCA2 loss of heterozygosity is found in almost all BRCA1 and BRCA2 carcinomas, respectively. Both genotypes have a low frequency of HER2 expression/amplification. In addition, comparative genomic hybridization and array expression studies have revealed differences in chromosomal gains and losses as well as expression patterns between genotypes. Several studies have shown that hereditary carcinomas that are not attributable to BRCA1/2 mutations are heterogeneous and have phenotypic similarities to BRCA2 tumors. A small group of cases are secondary to mutations in other breast cancer susceptibility genes, such as p53, PTEN or CDH1. As a result of the low frequency of breast carcinomas attributable to mutations in these genes, it is very difficult to establish a specific phenotype for each genotype, other than the association of lobular carcinomas with CDH1 germline mutations. The pathological and molecular features of hereditary breast cancer can drive specific treatments and influence the process of mutation screening.
TP53 Status and Response to Chemotherapy in Breast Cancer
Authors: Bertheau Philippe , Espié Marc , Turpin Elisabeth , Lehmann Jacqueline , Plassa Louis-François , Varna Mariana , Janin Anne , de Thé Hugues
Published: June 2008

Despite its central role in the control of apoptosis, senescence and cell cycle arrest, the tumor suppressor protein p53 remains an enigma for its possible role in predicting response to chemotherapy in cancer patients. Many studies remained inconclusive, others showed a better response for tumors with normal p53, and some recent studies showed adverse effects of normal p53 for response to treatment. p53 is not only a powerful pro-apoptotic factor in response to drug-induced DNA damages but also a potential inducer of cell cycle arrest, protecting tumor cells from further cytotoxic damages. Our review describes the classical as well as the more recent concepts. In order to draw definite conclusions, future works should use more reliable methods to assess the TP53 status and should address more homogeneous tumor subpopulations treated with homogeneous chemotherapy regimens.
Disseminated Tumor Cells in Bone Marrow and Circulating Tumor Cells in Blood of Breast Cancer Patients: Current State of Detection and Characterization
Authors: Riethdorf Sabine , Pantel Klaus
Published: June 2008

Despite the progress resulting from early detection and improved adjuvant therapy, the prognosis of breast cancer patients is still limited by the occurrence of distant metastases largely due to clinically occult micrometastases that remain undetected at primary diagnosis even by high-resolution imaging approaches. Recent research efforts have concentrated on the identification of additional parameters allowing individual risk assessment and stratification of patients for targeted therapies, since traditional prognostic factors are not sufficient to predict metastatic relapse and treatment decisions are still mainly based on statistical risk parameters. Highly sensitive and specific immunocytochemical and molecular assays now enable the detection and characterization of disseminated and circulating tumor cells (DTCs and CTCs, respectively) at the single cell level in bone marrow (BM) and peripheral blood, providing insights into the first crucial steps of the metastatic cascade. However, because of the still high variability of results in DTC/CTC detection, the necessity of standardized approaches will be discussed. A large number of studies showed that the presence of DTCs in BM has prognostic impact for primary breast cancer patients. DTCs are likely to escape from chemotherapy by maintaining a dormant nonproliferating state. There is also evidence for a stem cell-like phenotype of DTCs, probably contributing to the opportunity to escape from dormancy control and to start expansion to manifest metastases. Blood would also be an ideal source for the detection and monitoring of CTCs because of an easy noninvasive sampling procedure enabling repeated analyses. While prognostic significance of CTCs could be reliably demonstrated for metastatic breast cancer, studies to analyze the impact of CTCs in primary breast cancer patients and the potential to replace or supplement BM analysis are still ongoing. Furthermore, molecular characterization of CTCs might contribute to improving targeted and more individualized cancer therapies.
Molecular Analysis of Nipple Fluid for Breast Cancer Screening
Authors: Suijkerbuijk Karijn P.M. , van der Wall Elsken , Vooijs Marc , van Diest Paul J.
Published: June 2008

Lack of sensitivity and specificity of image-based breast cancer screening has urged the exploration of alternate screening modalities. Nipple fluid, which contains breast epithelial cells, is produced in small amounts in the breast ducts of nonlactating women and can be collected by noninvasive vacuum aspiration. After administration of nasal oxytocin, nipple aspiration yields sufficient material for molecular analysis in the large majority of women. Whereas nipple fluid cytology appears to have only a moderate correlation with breast cancer development, methylation holds promise as a more appropriate biomarker, since methylation aberrations occur as an early and frequent event during carcinogenesis. Using quantitative multiplex methylation-specific PCR, methylation can be detected in minute amounts of DNA extracted from nipple aspirates, precluding the need for more invasive intraductal approaches such as ductal lavage and random periareolar fine needle aspiration. The application of genomic and proteomic diagnostics to nipple aspirates therefore provides unprecedented opportunities for early breast cancer diagnosis amendable to population-based screening.
Karyotype analysis of the euploid cell population of a mouse embryonic stem cell line revealed a high incidence of chromosome abnormalities that varied during culture
Authors: Rebuzzini P. , Neri T. , Mazzini G. , Zuccotti M. , Redi C.A. , Garagna S.
Published: June 2008

It is common knowledge that mouse embryonic stem cell (mESC) lines accumulate chromosomal changes during culture. Despite the wide use of mESCs as a model of early mammalian development and cell differentiation, there is a lack of systematic studies aimed at characterizing their karyological changes during culture. We cultured an mESC line, derived in our laboratory, for a period of 3 months investigating its chromosome complement at different times. About 60% of the metaphases analysed were euploid throughout the culture period but, from passage 13, only 50% of the euploid metaphases had a proper chromosome complement. The remaining 50% showed chromosome abnormalities, mainly gain or loss of entire chromosomes, both within the same passage and among different passages analysed. The very heterogeneous spectrum of abnormalities indicates a high frequency of chromosome mutations that arise continuously during culture. The heterogeneity of the aberrant chromosome constitution of 2n = 40 metaphases, observed at different passages of culture, might be due either to their elimination or to a shift towards the hypoeu- or hypereuploid population of those metaphases that accumulate further chromosome abnormalities. The stability of the frequency of eu-, hypoeu- and hypereuploid populations during culture might, however, be due to the elimination of those cells that carry a high mutational burden. Based on our results, we suggest that karyotype analysis of the euploid cell population of mESC lines is necessary when such lines are used in the production of chimeric mice, for their contribution to the germ line, or when they are differentiated into specific cell types.
A comparative radiation hybrid map of sheep chromosome 10
Authors: Drögemüller M. , Tetens J. , Dalrymple B. , Goldammer T. , Wu C.H. , Cockett N.E. , Leeb T. , Drögemüller C.
Published: June 2008

Comparative radiation hybrid (RH) maps of individual ovine chromosomes are essential to identify genes governing traits of economic importance in sheep, a livestock species for which whole genome sequence data are not yet available. The USUoRH5000 radiation hybrid panel was used to generate a RH map of sheep chromosome 10 (OAR10) with 59 markers that span 1,422 cR over an estimated 92 Mb of the chromosome, thus providing markers every2 Mb (equivalent to every 24 cR). The markers were derived from 46 BAC end sequences (BESs), a single EST, and 12 microsatellites. Comparative analysis showed that OAR10 shares remarkable conservation of gene order along the entire length of cattle chromosome 12 and that OAR10 contains four major homologous synteny blocks, each related to segments of the homologous human chromosome 13. Extending the comparison to the horse, dog, mouse, and chicken genome showed that these blocks share conserved synteny across species.
Chromosomal localization of nine porcine genes encoding transcription factors involved in adipogenesis
Authors: Szczerbal I. , Chmurzynska A.
Published: June 2008

Chromosomal localization of nine porcine genes encoding transcription factors involved in adipogenesis was determined. BAC clones harboring sequences of selected genes CEBPA (SSC6q12), CEBPB (SSC17q23), CEBPD (SSC4q15), CEBPG (SSC6q12), PPARG (SSC13q24), SREBF1 (SSC10q17), DDIT3 (SSC12q15), GATA2 (SSC13q24 →q31) and GATA3 (SSC5p12) were mapped by FISH. The positions of these genes in the human and pig genomes were compared. A potential role of the genes encoding adipogenesis factors as candidate genes for fatness traits as well as obesity-related phenotypes is discussed.