bluuebunny/crossref_metadata_2025 huggingface dataset:
Expression of TRPC6 channels in human epithelial breast cancer cells
Authors: Guilbert Arnaud , Dhennin-Duthille Isabelle , Hiani Yassine EL , Haren Nathalie , Khorsi Hafida , Sevestre Henri , Ahidouch Ahmed , Ouadid-Ahidouch Halima
Published: August 2009

Background

TRP channels have been shown to be involved in tumour generation and malignant growth. However, the expression of these channels in breast cancer remains unclear. Here we studied the expression and function of endogenous TRPC6 channels in a breast cancer cell line (MCF-7), a human breast cancer epithelial primary culture (hBCE) and in normal and tumour breast tissues.

Methods

Molecular (Western blot and RT-PCR), and immunohistochemical techniques were used to investigate TRPC6 expression. To investigate the channel activity in both MCF-7 cells and hBCE we used electrophysiological technique (whole cell patch clamp configuration).

Results

A non selective cationic current was activated by the oleoyl-2-acetyl-sn-glycerol (OAG) in both hBCE and MCF-7 cells. OAG-inward current was inhibited by 2-APB, SK&F 96365 and La3+. TRPC6, but not TRPC7, was expressed both in hBCE and in MCF-7 cells. TRPC3 was only expressed in hBCE. Clinically, TRPC6 mRNA and protein were elevated in breast carcinoma specimens in comparison to normal breast tissue. Furthermore, we found that the overexpression of TRPC6 protein levels were not correlated with tumour grades, estrogen receptor expression or lymph node positive tumours.

Conclusion

Our results indicate that TRPC6 channels are strongly expressed and functional in breast cancer epithelial cells. Moreover, the overexpression of these channels appears without any correlation with tumour grade, ER expression and lymph node metastasis. Our findings support the idea that TRPC6 may have a role in breast carcinogenesis.
Management of SPN in France. Pathways for definitive diagnosis of solitary pulmonary nodule: a multicentre study in 18 French districts
Authors: Alzahouri Kazem , Velten Michel , Arveux Patrick , Woronoff-Lemsi Marie-Christine , Jolly Damien , Guillemin Francis
Published: August 2009

Background

The process of diagnosis and management of solitary pulmonary nodules (SPNs) between 1 and 3 cm is not standardized. This multicentre study investigated how diagnosis of newly discovered SPNs is managed in routine practice.

Methods

We examined 11,515 radiology reports of patients undergoing chest computed tomography (CT) at all 76 radiology centres in 18 French administrative districts covering 8,220,000 people. Information on diagnostic procedures and treatment administered from discovery to definitive diagnosis of SPN was collected prospectively.

Results

We identified 152 cases of newly diagnosed SPNs. Follow-up was complete for 112 patients. The median number of diagnostic tests was 4 and the mean time to diagnosis was 41.4 days. Marked variability was observed in the sequence of diagnostic tests, and 8 diagnostic pathways were identified. Patients' characteristics and radiological features of SPNs influenced the number of tests performed. Referral by specialist, history of smoking and spiculated SPN predicted the performance of at least one invasive procedure (P < 0.01). Definitive diagnosis was a malignant disease in 30 patients (26%).

Conclusion

The diagnosis of SPN is a complex process that physicians approach in markedly different ways. Implementing practice guidelines for managing the diagnosis of SPN requires clarification.
Chemokine receptor CXCR4 expression in hepatocellular carcinoma patients increases the risk of bone metastases and poor survival
Authors: Xiang Zuo-lin , Zeng Zhao-chong , Tang Zhao-you , Fan Jia , Zhuang Peng-yuan , Liang Ying , Tan Yun-shan , He Jian
Published: August 2009

Background

The chemokine and bone marrow-homing receptor CXCR4 is implicated in metastases of various cancers. This study was conducted to analyze the association of CXCR4 expression with hepatocellular carcinoma (HCC) bone metastasis and patient survival.

Methods

Tumor tissue from HCC patients with (n = 43) and without (n = 138) bone metastasis was subjected to immunohistochemical staining for CXCR4 using tissue microarrays. Immunoreactivity was evaluated semi-quantitatively. A receiver-operating characteristic-based approach and logistical regression analysis were used to determine the predictive value of clinicopathologic factors, including CXCR4 expression, in bone metastasis. Patient survival was analyzed by Kaplan-Meier curves and log-rank tests.

Results

CXCR4 overexpression was detected in 34 of 43 (79.1%) patients with bone metastases and in 57 of 138 (41.3%) without bone metastases. CXCR4 expression correlated with (correlation coefficient: 0.551, P < 0.001) and was predictive of HCC bone metastases (AUC: 0.689; 95%CI: 0.601 – 0.776; P < 0.001). CXCR4 staining intensity correlated with the bone metastasis-free survival (correlation coefficient: -0.359; P = 0.018). CXCR4 overexpression in primary tumors (n = 91) decreased overall median survival (18.0 months vs. 36.0 months, P <0.001). Multivariable analysis identified CXCR4 as a strong, independent risk factor for reduced disease-free survival (relative risk [RR]: 5.440; P = 0.023) and overall survival (RR: 7.082; P = 0.001).

Conclusion

CXCR4 expression in primary HCCs may be an independent risk factor for bone metastasis and may be associated with poor clinical outcome.
The TGFBR1*6A allele is not associated with susceptibility to colorectal cancer in a Spanish population: a case-control study
Authors: Castillejo Adela , Mata-Balaguer Trinidad , Montenegro Paola , Ochoa Enrique , Lázaro Rafael , Martínez-Cantó Ana , Castillejo María-Isabel , Guarinos Carla , Barberá Víctor-Manuel , Guillén-Ponce Carmen , Carrato Alfredo , Soto José-Luís
Published: August 2009

Background

TGF-β receptor type I is a mediator of growth inhibitory signals. TGFBR1*6A (rs11466445) is a common polymorphic variant of the TGF-β receptor I gene and has been associated with tumour susceptibility. Nevertheless, the role of this polymorphism as a risk factor for colorectal cancer is controversial. The aim of this study was to assess the association between TGFBR1*6A and colorectal cancer, age, sex, tumour location and tumour stage in a Spanish population.

Methods

The case-control study involved 800 Spanish subjects: 400 sporadic colorectal cancer patients and 400 age-, sex-, and ethnic-matched controls. The odds ratio (OR) and 95% confidence interval (95% CI) for the TGFBR1*6A polymorphism were calculated using unconditional logistic regression adjusted for age and sex. Analysis of somatic mutations at the GCG repeat of TGFBR1 exon 1 and germline allele-specific expression were also conducted to obtain further information on the contribution of the TGFBR1*6A allele to CRC susceptibility.

Results

There was no statistically significant association between the TGFBR1*6A allele and CRC (p > 0.05). The OR was 1.147 (95% CI: 0.799–1.647) for carriers of the TGFBR1*6A allele and 0.878 (95% CI: 0.306–2.520) for homozygous TGFBR1*6A individuals compared with the reference. The frequency of the polymorphism was not affected by age, sex or tumour stage. The TGFBR1*6A allele was more prevalent among colon tumour patients than among rectal tumour patients. Tumour somatic mutations were found in only two of 69 cases (2.9%). Both cases involved a GCG deletion that changed genotype 9A/9A in normal DNA to genotype 9A/8A. Interestingly, these two tumours were positive for microsatellite instability, suggesting that these mutations originated because of a deficient DNA mismatch repair system.

Allele-specific expression of the 9A allele was detected in seven of the 14 heterozygous 9A/6A tumour cases. This could have been caused by linkage disequilibrium of the TGFBR1*6A allele with mutations that cause allele-specific expression, as was recently suggested.

Conclusion

Our results suggest that the TGFBR1*6A allele does not confer an increased risk of colorectal cancer in the Spanish population.
Selected hematologic and biochemical measurements in African HIV-infected and uninfected pregnant women and their infants: the HIV Prevention Trials Network 024 protocol
Authors: Mwinga Kasonde , Vermund Sten H , Chen Ying Q , Mwatha Anthony , Read Jennifer S , Urassa Willy , Carpenetti Nicole , Valentine Megan , Goldenberg Robert L
Published: August 2009

Background

Reference values for hematological and biochemical assays in pregnant women and in newborn infants are based primarily on Caucasian populations. Normative data are limited for populations in sub-Saharan Africa, especially comparing women with and without HIV infection, and comparing infants with and without HIV infection or HIV exposure.

Methods

We determined HIV status and selected hematological and biochemical measurements in women at 20–24 weeks and at 36 weeks gestation, and in infants at birth and 4–6 weeks of age. All were recruited within a randomized clinical trial of antibiotics to prevent chorioamnionitis-associated mother-to-child transmission of HIV (HPTN024). We report nearly complete laboratory data on 2,292 HIV-infected and 367 HIV-uninfected pregnant African women who were representative of the public clinics from which the women were recruited. Nearly all the HIV-infected mothers received nevirapine prophylaxis at the time of labor, as did their infants after birth (always within 72 hours of birth, but typically within just a few hours at the four study sites in Malawi (2 sites), Tanzania, and Zambia.

Results

HIV-infected pregnant women had lower red blood cell counts, hemoglobin, hematocrit, and white blood cell counts than HIV-uninfected women. Platelet and monocyte counts were higher among HIV-infected women at both time points. At the 4–6-week visit, HIV-infected infants had lower hemoglobin, hematocrit and white blood cell counts than uninfected infants. Platelet counts were lower in HIV-infected infants than HIV-uninfected infants, both at birth and at 4–6 weeks of age. At 4–6 weeks, HIV-infected infants had higher alanine aminotransferase measures than uninfected infants.

Conclusion

Normative data in pregnant African women and their newborn infants are needed to guide the large-scale HIV care and treatment programs being scaled up throughout the continent. These laboratory measures will help interpret clinical data and assist in patient monitoring in a sub-Saharan Africa context.

Trial Registration

nicalTrials.gov Identifier NCT00021671.
Italian multicenter study on infection hazards during dental practice: Control of environmental microbial contamination in public dental surgeries
Authors: Castiglia Paolo , Liguori Giorgio , Montagna Maria Teresa , Napoli Christian , Pasquarella Cesira , Bergomi Margherita , Fabiani Leila , Monarca Silvano , Petti Stefano ,   SItI Working Group Hygiene in Dentistry
Published: August 2009

Background

The present study assessed microbial contamination in Italian dental surgeries.

Methods

An evaluation of water, air and surface microbial contamination in 102 dental units was carried out in eight Italian cities.

Results

The findings showed water microbial contamination in all the dental surgeries; the proportion of water samples with microbial levels above those recommended decreased during working. With regard to Legionella spp., the proportion of positive samples was 33.3%. During work activity, the index of microbial air contamination (IMA) increased. The level of microbial accumulation on examined surfaces did not change over time.

Conclusion

These findings confirm that some Italian dental surgeries show high biocontamination, as in other European Countries, which highlights the risk of occupational exposure and the need to apply effective measures to reduce microbial loads.
Why do Asian-American women have lower rates of breast conserving surgery: results of a survey regarding physician perceptions
Authors: Pham Jane T , Allen Laura J , Gomez Scarlett L
Published: August 2009

Background

US Asian women with early-stage breast cancer are more likely to receive a modified radical mastectomy (MRM) than White women, contrary to clinical recommendations regarding breast conserving treatment (BCT).

Methods

We surveyed physicians regarding treatment decision-making for early-stage breast cancer, particularly as it applies to Asian patients. Physicians were identified through the population-based Greater Bay Area Cancer Registry. Eighty (of 147) physicians completed a questionnaire on sociodemographics, professional training, clinical practices, and perspectives on the treatment decision-making processes.

Results

The most important factors identified by physicians in the BCT/MRM decision were clinical in nature, including presence of multifocal disease (86% identified this as being an important factor for selecting MRM), tumor size (71% for MRM, 78% for BCT), cosmetic result (74% for BCT), and breast size (50% for MRM, 55% for BCT). The most important reasons cited for the Asian treatment patterns were patient attitudes toward not needing to preserve the breast (53%), smaller breast sizes (25%), and fear and cultural beliefs (12%).

Conclusion

These survey results suggest that physicians perceive major roles of both clinical and cultural factors in the BCT/MRM decision, but cultural factors may be more relevant in explaining surgical treatment patterns among Asians.
Fluid lavage in patients with open fracture wounds (FLOW): an international survey of 984 surgeons
Authors: Petrisor Brad , Jeray Kyle , Schemitsch Emil , Hanson Beate , Sprague Sheila , Sanders David , Bhandari Mohit ,   the FLOW Investigators
Published: August 2009

Background

Although surgeons acknowledge the importance of irrigating open fracture wounds, the choice of irrigating fluid and delivery pressure remains controversial. Our objective was to clarify current opinion with regard to the irrigation of open fracture wounds.

Methods

We used a cross-sectional survey and a sample-to-redundancy strategy to examine surgeons' preferences in the initial management of open fracture wounds. We mailed this survey to members of the Canadian Orthopaedic Association and delivered it to attendees of an international fracture course (AO, Davos, Switzerland).

Results

Of the 1,764 surgeons who received the questionnaire, 984 (55.8%) responded. In the management of open wounds, the majority of surgeons surveyed, 676 (70.5%), favoured normal saline alone. Bacitracin solution was used routinely by only 161 surgeons (16.8%). The majority of surgeons, 695 (71%) used low pressures when delivering the irrigating solution to the wound. There was, however considerable variation in what pressures constituted high versus low pressure lavage. The overwhelming majority of surgeons, 889 (94.2%), reported they would change their practice if a large randomized controlled trial showed a clear benefit of an irrigating solution – especially if it was different from the solution they used.

Conclusion

The majority of surgeons favour both normal saline and low pressure lavage for the initial management of open fracture wounds. However, opinions varied as regards the comparative efficacy of different solutions, the use of additives and high versus low pressure. Surgeons have expressed considerable support for a trial evaluating both irrigating solutions and pressures.
Beyond blood brain barrier breakdown – in vivodetection of occult neuroinflammatory foci by magnetic nanoparticles in high field MRI
Authors: Tysiak Eva , Asbach Patrick , Aktas Orhan , Waiczies Helmar , Smyth Maureen , Schnorr Joerg , Taupitz Matthias , Wuerfel Jens
Published: August 2009

Background

Gadopentate dimeglumine (Gd-DTPA) enhanced magnetic resonance imaging (MRI) is widely applied for the visualization of blood brain barrier (BBB) breakdown in multiple sclerosis and its animal model, experimental autoimmune encephalomyelitis (EAE). Recently, the potential of magnetic nanoparticles to detect macrophage infiltration by MRI was demonstrated. We here investigated a new class of very small superparamagnetic iron oxide particles (VSOP) as novel contrast medium in murine adoptive-transfer EAE.

Methods

EAE was induced in 17 mice via transfer of proteolipid protein specific T cells. MR images were obtained before and after application of Gd-DTPA and VSOP on a 7 Tesla rodent MR scanner. The enhancement pattern of the two contrast agents was compared, and correlated to histology, including Prussian Blue staining for VSOP detection and immunofluorescent staining against IBA-1 to identify macrophages/microglia.

Results

Both contrast media depicted BBB breakdown in 42 lesions, although differing in plaques appearances and shapes. Furthermore, 13 lesions could be exclusively visualized by VSOP. In the subsequent histological analysis, VSOP was localized to microglia/macrophages, and also diffusely dispersed within the extracellular matrix.

Conclusion

VSOP showed a higher sensitivity in detecting BBB alterations compared to Gd-DTPA enhanced MRI, providing complementary information of macrophage/microglia activity in inflammatory plaques that has not been visualized by conventional means.
Vision based interface system for hands free control of an intelligent wheelchair
Authors: Ju Jin Sun , Shin Yunhee , Kim Eun Yi
Published: August 2009

Background

Due to the shift of the age structure in today's populations, the necessities for developing the devices or technologies to support them have been increasing. Traditionally, the wheelchair, including powered and manual ones, is the most popular and important rehabilitation/assistive device for the disabled and the elderly. However, it is still highly restricted especially for severely disabled. As a solution to this, the Intelligent Wheelchairs (IWs) have received considerable attention as mobility aids. The purpose of this work is to develop the IW interface for providing more convenient and efficient interface to the people the disability in their limbs.

Methods

This paper proposes an intelligent wheelchair (IW) control system for the people with various disabilities. To facilitate a wide variety of user abilities, the proposed system involves the use of face-inclination and mouth-shape information, where the direction of an IW is determined by the inclination of the user's face, while proceeding and stopping are determined by the shapes of the user's mouth. Our system is composed of electric powered wheelchair, data acquisition board, ultrasonic/infra-red sensors, a PC camera, and vision system. Then the vision system to analyze user's gestures is performed by three stages: detector, recognizer, and converter. In the detector, the facial region of the intended user is first obtained using Adaboost, thereafter the mouth region is detected based on edge information. The extracted features are sent to the recognizer, which recognizes the face inclination and mouth shape using statistical analysis andK-means clustering, respectively. These recognition results are then delivered to the converter to control the wheelchair.

Result & conclusion

The advantages of the proposed system include 1) accurate recognition of user's intention with minimal user motion and 2) robustness to a cluttered background and the time-varying illumination. To prove these advantages, the proposed system was tested with 34 users in indoor and outdoor environments and the results were compared with those of other systems, then the results showed that the proposed system has superior performance to other systems in terms of speed and accuracy. Therefore, it is proved that proposed system provided a friendly and convenient interface to the severely disabled people.
Proinflammatory-Activated Trigeminal Satellite Cells Promote Neuronal Sensitization: Relevance for Migraine Pathology
Authors: Capuano Alessandro , De Corato Alice , Lisi Lucia , Tringali Giuseppe , Navarra Pierluigi , Russo Cinzia Dello
Published: August 2009

Background

Migraine is a complex, chronic, painful, neurovascular disorder characterized by episodic activation of the trigeminal system. Increased levels of calcitonin gene-related peptide (CGRP) are found at different levels during migraine attacks. Interestingly, CGRP is also released within the trigeminal ganglia suggesting possible local effects on satellite cells, a specialized type of glia that ensheaths trigeminal neurons. CGRP was shown to enhance satellite-cell production of interleukin 1β (IL-1β), while trigeminal neurons express an activity-dependent production of nitric oxide (NO). Thus, in the present study we tested the hypothesis that IL-1β and NO induce trigeminal satellite cell activation, and that once activated these cells can influence neuronal responses.

Results

Primary cultures of rat trigeminal satellite cells isolated from neuronal cultures were characterized in vitro. Cyclooxygenase (COX) expression and activity were taken as a marker of glial pro-inflammatory activation. Most of the experiments were carried out to characterize satellite cell responses to the two different pro-inflammatory stimuli. Subsequently, medium harvested from activated satellite cells was used to test possible modulatory effects of glial factors on trigeminal neuronal activity. IL-1β and the NO donor diethylenetriamine/nitric oxide (DETA/NO) elevated PGE2 release by satellite cells. The stimulatory effect of IL-1β was mediated mainly by upregulation of the inducible form of COX enzyme (COX2), while NO increased the constitutive COX activity. Regardless of the activator used, it is relevant that short exposures of trigeminal satellite cells to both activators induced modifications within the cells which led to significant PGE2 production after removal of the pro-inflammatory stimuli. This effect allowed us to harvest medium from activated satellite cells (so-called ‘conditioned medium’) that did not contain any stimulus, and thus test the effects of glial factors on neuronal activation. Conditioned medium from satellite cells activated by either IL-1β or NO augmented the evoked release of CGRP by trigeminal neurons.

Conclusion

These findings indicate that satellite cells contribute to migraine-related neurochemical events and are induced to do so by autocrine/paracrine stimuli (such as IL-1β and NO). The responsiveness of IL-1β to CGRP creates the potential for a positive feedback loop and, thus, a plurality of targets for therapeutic intervention in migraine.
Mandibular prognathism caused by acromegaly – a surgical orthodontic case
Authors: Gosau Martin , Vogel Corinna , Moralis Antonios , Proff Peter , Kleinheinz Johannes , Driemel Oliver
Published: August 2009

A 22-year-old man presented for orthodontic surgery because of mandibular prognathism. Clinical symptoms suggested acromegaly, and diagnosis was verified by an endocrinologist as well as by radiograph. Bilateral mandibular prognathism often represents the first and most striking physical characteristic of acromegaly; usually, it is also the main reason why patients seek help from orthodontists or maxillo-facial surgeons. This case report recapitulates the clinical and histopathological findings in pituitary growth hormone (GH) adenomas and emphasises their importance in surgical orthodontic planning. Mandibular prognatism, macroglossia and abnormal growth of hands and feet represent strong indicators for the diagnosis of acromegaly. This disease and its complications not only affect the entire body but increase mortality if the pituitary gland tumour remains untreated.
Spinal Subdural Staphylococcus Aureus Abscess: case report and review of the literature
Authors: Velissaris Dimitris , Aretha Diamanto , Fligou Fotini , Filos Kriton S
Published: August 2009

Background

Only 65 cases (including our case) of spinal subdural abscesses have been reported to the literature, mostly to the lumbar spine. Staphylococcus aureus is the most common bacterial. The symptoms are not caracteristic and contrast – enhanced magnetic resonance imaging scan (MRI) is the imaging method of choice. The early diagnosis is crucial for the prognosis of the patient.

Case presentation

We present a patient 75 years old who had a history of diabetes and suffered acute low back pain in the region of the lumbar spine for the last 4 days before his admission to the hospital. He also experienced lower leg weakness, fever and neck stiffness. After having a brain CT scan and a lumbar puncture the patient hospitalized with the diagnosis of meningitis. Five days after his admission the diagnosis of subdural abscess secured with contrast – enhanced MRI but meanwhile the condition of the patient impaired with respiratory failure and quadriplegia and he was admitted to the ICU. A laminectomy was performed eight days after his admission into the hospital but unfortunately the patient died.

Conclusion

Early diagnosis and treatment are very important for the good outcome in patients with subdural abscess. Although morbidity and mortality are very high, surgical and antibiotic treatment should be established as soon as possible after the diagnosis has secured.
Application of molecular cytogenetic techniques to clarify apparently balanced complex chromosomal rearrangements in two patients with an abnormal phenotype: case report
Authors: de Vree Paula JP , Simon Marleen EH , van Dooren Marieke F , Stoevelaar Gerda HT , Hilkmann José TW , Rongen Michel A , Huijbregts Gido CM , Verkerk Annemieke JMH , Poddighe Pino J
Published: August 2009

Background

Complex chromosomal rearrangements (CCR) are rare cytogenetic findings that are difficult to karyotype by conventional cytogenetic analysis partially because of the relative low resolution of this technique. High resolution genotyping is necessary in order to identify cryptic imbalances, for instance near the multiple breakpoints, to explain the abnormal phenotype in these patients. We applied several molecular techniques to elucidate the complexity of the CCRs of two adult patients with abnormal phenotypes.

Results

Multicolour fluorescence in situ hybridization (M-FISH) showed that in patient 1 the chromosomes 1, 10, 15 and 18 were involved in the rearrangement whereas for patient 2 the chromosomes 5, 9, 11 and 13 were involved. A 250 k Nsp1 SNP-array analysis uncovered a deletion in chromosome region 10p13 for patient 1, harbouring 17 genes, while patient 2 showed no pathogenic gains or losses. Additional FISH analysis with locus specific BAC-probes was performed, leading to the identification of cryptic interstitial structural rearrangements in both patients.

Conclusion

Application of M-FISH and SNP-array analysis to apparently balanced CCRs is useful to delineate the complex chromosomal rearrangement in detail. However, it does not always identify cryptic imbalances as an explanation for the abnormal phenotype in patients with a CCR.
Host sequence motifs shared by HIV predict response to antiretroviral therapy
Authors: Dampier William , Evans Perry , Ungar Lyle , Tozeren Aydin
Published: August 2009

Background

The HIV viral genome mutates at a high rate and poses a significant long term health risk even in the presence of combination antiretroviral therapy. Current methods for predicting a patient's response to therapy rely on site-directed mutagenesis experiments andin vitroresistance assays. In this bioinformatics study we treat response to antiretroviral therapy as a two-body problem: response to therapy is considered to be a function of both the host and pathogen proteomes. We set out to identify potential responders based on the presence or absence of host protein and DNA motifs on the HIV proteome.

Results

An alignment of thousands of HIV-1 sequences attested to extensive variation in nucleotide sequence but also showed conservation of eukaryotic short linear motifs on the protein coding regions. The reduction in viral load of patients in the Stanford HIV Drug Resistance Database exhibited a bimodal distribution after 24 weeks of antiretroviral therapy, with 2,000 copies/ml cutoff. Similarly, patients allocated into responder/non-responder categories based on consistent viral load reduction during a 24 week period showed clear separation. In both cases of phenotype identification, a set of features composed of short linear motifs in the reverse transcriptase region of HIV sequence accurately predicted a patient's response to therapy. Motifs that overlap resistance sites were highly predictive of responder identification in single drug regimens but these features lost importance in defining responders in multi-drug therapies.

Conclusion

HIV sequence mutates in a way that preferentially preserves peptide sequence motifs that are also found in the human proteome. The presence and absence of such motifs at specific regions of the HIV sequence is highly predictive of response to therapy. Some of these predictive motifs overlap with known HIV-1 resistance sites. These motifs are well established in bioinformatics databases and hence do not require identification viain vitromutation experiments.
Integrated microarray and multiplex cytokine analyses of Kaposi's Sarcoma Associated Herpesvirus viral FLICE Inhibitory Protein K13 affected genes and cytokines in human blood vascular endothelial cells
Authors: Punj Vasu , Matta Hittu , Schamus Sandra , Chaudhary Preet M
Published: August 2009

Background

Kaposi's sarcoma (KS) associated herpesvirus (KSHV) is the etiological agent of KS, a neoplasm characterized by proliferating spindle cells, extensive neoangiogenesis and a prominent inflammatory infiltrate. Infection of blood vascular endothelial cells with KSHV in vitro results in their spindle cell transformation, which is accompanied by increased expression of inflammatory chemokines and cytokines, and acquisition of lymphatic endothelial markers. Mimicking the effect of viral infection, ectopic expression of KSHV-encoded latent protein vFLIP K13 is sufficient to induce spindle transformation of vascular endothelial cells. However, the effect of K13 expression on global gene expression and induction of lymphatic endothelial markers in vascular endothelial cells has not been studied.

Methods

We used gene array analysis to determine change in global gene expression induced by K13 in human vascular endothelial cells (HUVECs). Results of microarray analysis were validated by quantitative RT-PCR, immunoblotting and a multiplex cytokine array.

Results

K13 affected the expression of several genes whose expression is known to be modulated by KSHV infection, including genes involved in immune and inflammatory responses, anti-apoptosis, stress response, and angiogenesis. The NF-κB pathway was the major signaling pathway affected by K13 expression, and genetic and pharmacological inhibitors of this pathway effectively blocked K13-induced transcriptional activation of the promoter of CXCL10, one of the chemokines whose expression was highly upregulated by K13. However, K13, failed to induce expression of lymphatic markers in blood vascular endothelial cells.

Conclusion

While K13 may account for change in the expression of a majority of genes observed following KSHV infection, it is not sufficient for inducing lymphatic reprogramming of blood vascular endothelial cells.
CDX2 hox gene product in a rat model of esophageal cancer
Authors: Ingravallo Giuseppe , Dall'Olmo Luigi , Segat Daniela , Fassan Matteo , Mescoli Claudia , Dazzo Emanuela , Castoro Carlo , Polimeno Lorenzo , Rizzetto Christian , Baroni Maurizio David , Zaninotto Giovanni , Ancona Ermanno , Rugge Massimo
Published: August 2009

Background

Barrett's mucosa is the precursor of esophageal adenocarcinoma. The molecular mechanisms behind Barrett's carcinogenesis are largely unknown. Experimental models of longstanding esophageal reflux of duodenal-gastric contents may provide important information on the biological sequence of the Barrett's oncogenesis.

Methods

The expression of CDX2 hox-gene product was assessed in a rat model of Barrett's carcinogenesis. Seventy-four rats underwent esophago-jejunostomy with gastric preservation. Excluding perisurgical deaths, the animals were sacrificed at various times after the surgical treatment (Group A: <10 weeks; Group B: 10–30 weeks; Group C: >30 weeks).

Results

No Cdx2 expression was detected in either squamous epithelia of the proximal esophagus or squamous cell carcinomas. De novo Cdx2 expression was consistently documented in the proliferative zone of the squamous epithelium close to reflux ulcers (Group A: 68%; Group B: 64%; Group C: 80%), multilayered epithelium and intestinal metaplasia (Group A: 9%; Group B: 41%; Group C: 60%), and esophageal adenocarcinomas (Group B: 36%; Group C: 35%). A trend for increasing overall Cdx2 expression was documented during the course of the experiment (p = 0.001).

Conclusion

De novo expression of Cdx2 is an early event in the spectrum of the lesions induced by experimental gastro-esophageal reflux and should be considered as a key step in the morphogenesis of esophageal adenocarcinoma.
The cytotoxicity of γ-secretase inhibitor I to breast cancer cells is mediated by proteasome inhibition, not by γ-secretase inhibition
Authors: Han Jianxun , Ma Ivy , Hendzel Michael J , Allalunis-Turner Joan
Published: August 2009

Introduction

Notch is a family of transmembrane protein receptors whose activation requires proteolytic cleavage by γ-secretase. Since aberrant Notch signaling can induce mammary carcinomas in transgenic mice and high expression levels of Notch receptors and ligands correlates with overall poor clinical outcomes, inhibiting γ-secretase with small molecules may be a promising approach for breast cancer treatment. Consistent with this hypothesis, two recent papers reported that γ-secretase inhibitor I (GSI I), Z-LLNle-CHO, is toxic to breast cancer cells both in vitro and in vivo. In this study, we compared the activity and cytotoxicity of Z-LLNle-CHO to that of two highly specific GSIs, DAPT and L-685,458 and three structurally unrelated proteasome inhibitors, MG132, lactacystin, and bortezomib in order to study the mechanism underlying the cytotoxicity of Z-LLNle-CHO in breast cancer cells.

Methods

Three estrogen receptor (ER) positive cell lines, MCF-7, BT474, and T47D, and three ER negative cell lines, SKBR3, MDA-MB-231, and MDA-MB-468, were used in this study. Both SKBR3 and BT474 cells also overexpress HER2/neu. Cytotoxicity was measured by using an MTS cell viability/proliferation assay. Inhibition of γ-secretase activity was measured by both immunoblotting and immunofluorescent microscopy in order to detect active Notch1 intracellular domain. Proteasome inhibition was determined by using a cell-based proteasome activity assay kit, by immunoblotting to detect accumulation of polyubiquitylated protein, and by immunofluorescent microscopy to detect redistribution of cellular ubiquitin.

Results

We found that blocking γ-secretase activity by DAPT and L-685,458 had no effect on the survival and proliferation of a panel of six breast cancer cell lines while Z-LLNle-CHO could cause cell death even at concentrations that inhibited γ-secretase activity less efficiently. Furthermore, we observed that Z-LLNle-CHO could inhibit proteasome activity and the relative cellular sensitivity of these six breast cancer cell lines to Z-LLNle-CHO was the same as observed for three proteasome inhibitors. Finally, we found that the cell killing effect of Z-LLNle-CHO could be reversed by a chemical that restored the proteasome activity.

Conclusions

We conclude that the cytotoxicity of Z-LLNle-CHO in breast cancer cells is mediated by proteasome inhibition, not by γ-secretase inhibition.
Short-term outcomes of cadaveric lung transplantation in ventilator-dependent patients
Authors: Hsu Hsao-Hsun , Chen Jin-Shing , Ko Wen-Je , Huang Shu-Chien , Kuo Shuenn-Wen , Huang Pei-Ming , Chi Nai-Hsin , Chang Chin-Chih , Chen Robert J , Lee Yung-Chie
Published: August 2009

Introduction

Survival after cadaveric lung transplantation (LTx) in respiratory failure recipients who were already dependent on ventilation support prior to transplantation is poor, with a relatively high rate of surgical mortality and morbidity. In this study, we sought to describe the short-term outcomes of bilateral sequential LTx (BSLTx) under extracorporeal membrane oxygenation (ECMO) support in a consecutive series of preoperative respiratory failure patients.

Methods

Between July 2006 and July 2008, we performed BSLTx under venoarterious (VA) ECMO support in 10 respiratory failure patients with various lung diseases. Prior to transplantation, 6 patients depended on invasive mechanical ventilation support and the others (40%) needed noninvasive positive pressure ventilation to maintain adequate gas exchange. Their mean age was 40.9 years and the mean observation period was 16.4 months.

Results

Except for 1 ECMO circuit that had been set up in the intensive care unit for pulmonary crisis 5 days prior to transplantation, most ECMO (90%) circuits were set up in the operating theater prior to pneumonectomy of native lung during transplantation. Patients were successfully weaned off ECMO circuits immediately after transplantation in 8 cases, and within 1 day (1/10 patients) and after 9 days (1/10 patients) due to severe reperfusion lung edema following transplantation. The mean duration of ECMO support in those successfully weaned off in the operating theater (n = 8) was 7.8 hours. The average duration of intensive care unit stay (n = 10) was 43.1 days (range, 35 to 162 days) and hospital stay (n = 10) was 70 days (range, 20 to 86 days). Although 4 patients (40%) had different degrees of complicated postoperative courses unrelated to ECMO, all patients were discharged home postoperatively. The mean forced vital capacity and the forced expiratory volume in 1 second both increased significantly postoperatively. The cumulative survival rates at 3 months and at 12 months post-transplantation were 100% and 90%.

Conclusions

Although BSLTx in this critical population has varied surgical complications and prolonged length of postoperative ICU and hospital stays, all the patients observed in this study could tolerate the transplant procedures under VA ECMO support with promising pulmonary function and satisfactory short-term outcome.
Shake Map Methodology for Intermediate-Depth Vrancea (Romania) Earthquakes
Authors: Böse Maren , Sokolov Vladimir , Wenzel Friedemann
Published: August 2009

We establish and test a shake map methodology for intermediate-depth Vrancea earthquakes, based on seismological information gathered in Romania during recent years. We use region- (azimuth-) dependent attenuation relations derived from stochastic simulations of ground motions using spectral models of Vrancea earthquakes. Both region boundaries and Fourier amplification spectra for the characterization of seismic site effects are based on several hundred weak, moderate and strong-motion records and macroseismic intensity maps. We determine region-specific, magnitude- and distance-dependent amplification factors of peak values and instrumental intensity relative to rock. We interpolate recorded ground motions and ground motion estimates from the obtained amplification factors and attenuation relations for rock conditions. The resulting shake maps show a good agreement with macroseismic descriptions of moderate-sized and large Vrancea earthquakes, demonstrating the feasibility of a seismological approach to shake map generation. Unlike previous methodologies, this approach requires neither expensive assessments of geology-dependent site amplification factors, nor large numbers of strong-motion records. Our results are in good agreement with empirical topographic slope-site amplification relations, but give a better reflection of the abnormal attenuation of seismic waves in the Transylvanian region and the strong amplification in the Focsani basin.
Seismic Response of Levees in the Sacramento-San Joaquin Delta
Authors: Kishida Tadahiro , Boulanger Ross W. , Abrahamson Norman A. , Driller Michael W. , Wehling Timothy M.
Published: August 2009

The seismic response of levees in the Sacramento-San Joaquin Delta, where the subsurface soils include thick deposits of highly organic soils, is evaluated. One-dimensional (1-D) and two-dimensional (2-D) equivalent-linear analyses were performed that accounted for variability in ground motions, dynamic properties, and soil profiles. Regression models were developed for: (1) the ratio of spectral accelerations at levee crests computed by 2-D versus 1-D response analyses, (2) stress reduction factors from 1-D site response analyses and seismic coefficient reduction factors for various failure surface depths from the 2-D response analyses, and (3) Newmark sliding block displacements computed for the input NEHRP site D ground motions and the computed seismic coefficient time series. The results of these regression models are compared to those obtained in previous studies involving different soil conditions, geometries, and motions. Newmark sliding block displacement hazard curves were calculated for a representative site in the Sacramento-San Joaquin Delta, and the contributions of various uncertainties to the displacement hazard curves are described.
Socioeconomic Clustering in Seismic Risk Assessment of Urban Housing Stock
Authors: Prasad J. S.R. , Singh Yogendra , Kaynia Amir M. , Lindholm Conrad
Published: August 2009

A seismic risk assessment methodology based on socioeconomic clustering of urban habitat is presented in this paper. In this methodology, the city is divided into different housing clusters based on socioeconomic level of occupants, representing reasonably uniform seismic risk. It makes an efficient utilization of high resolution satellite data and stratified random sample survey to develop the building stock database. Ten different classes of socioeconomic clusters found in Indian cities are defined and 34 model building types (MBTs) prevalent on the Indian subcontinent have been identified and compared with the Medvedev-Sponheuer-Karnik (MSK) scale, European macroseismic scale (EMS), parameterless scale of seismic intensity (PSI), and HAZUS classifications. Lower and upper bound damage probability matrices (DPMs) are estimated, based on the MSK and EMS intensity scales and experience from past earthquakes in India. A case study of Dehradun, a city in the foothills of Himalayas, is presented. The risk estimates using the estimated DPMs have been compared with those obtained using the PSI scale. It has been observed that poorer people are subjected to higher seismic risk, both in terms of casualties and in terms of percent economic losses.
Direct Displacement Procedure for Performance-Based Seismic Design of Mid-Rise Wood-Framed Structures
Authors: Pang Wei Chiang , Rosowsky David V.
Published: August 2009

This paper presents a direct displacement design (DDD) procedure that can be used for seismic design of multistory wood-framed structures. The proposed procedure is applicable to any pure shear deforming system. The design procedure is a promising design tool for performance-based seismic design since it allows consideration of multiple performance objectives (e.g., damage limitation, safety requirements) without requiring the engineer to perform a complex finite element or nonlinear time-history analysis of the complete structure. A simple procedure based on normalized modal analysis is used to convert the code-specified acceleration response spectrum into a set of interstory drift spectra. These spectra can be used to determine the minimum stiffness required for each floor based on the drift limit requirements. Specific shear walls can then be directly selected from a database of backbone curves. The procedure is illustrated on the design of two three-story ATC-63 archetype buildings, and the results are validated using nonlinear time-history analysis.
Orientation of Maximum Spectral Demand in the Near-Fault Region
Authors: Huang Yin-Nan , Whittaker Andrew S. , Luco Nicolas
Published: August 2009

An orientation-dependent parameter, [Formula: see text], is used to investigate the orientation of maximum elastic spectral demand for near-fault ground motions. The upper bound on [Formula: see text], equal to 1, occurs when the spectral demands for an orientation [Formula: see text] are equal to the maximum demands at all periods considered. One hundred forty-seven pairs of near-fault ground motions were used to identify the orientation associated with the maximum value of [Formula: see text] for each pair of ground motions. The maximum value of [Formula: see text] is greater than 0.9 for over 80% of the records in the dataset, meaning that there is generally an axis where the spectral demands are equal or very close to the maximum spectral demands for a wide range of period. The strike-normal direction should not be used as a surrogate for the direction of maximum shaking for a) closest site-to-source distance less than [Formula: see text] and periods less than [Formula: see text], and b) closest site-to-source distance greater than [Formula: see text].
Seismic Hazard Mapping for Italy in Terms of Broadband Displacement Response Spectra
Authors: Faccioli Ezio , Villani Manuela
Published: August 2009

A new representation of seismic hazard is proposed for Italy based on displacement elastic response spectra in a vibration period range that extends from [Formula: see text]. This relies on an available seismotectonic zonation and earthquake catalogue, but makes use of a set of very recent, expressly developed attenuation relations. The long period picture of ground motion hazard is illustrated vis-à-vis the conventional one based on ground acceleration, and the feasibility of simple approximations of the displacement spectra, useful for design purposes, is shown. We give some foresight on the differences to be expected in hazard maps resulting from the use of a predominantly fault-based seismic source model, as opposed to the more conventional model that includes only spatially extended zones. Finally, we highlight the different hazard exposure of different regions depending on whether we represent hazard with a long or a short period parameter and we discuss the adequacy of recent code provisions regarding elastic displacement spectra.
Direct Calculation of the Probability Distribution for Earthquake Losses to a Portfolio
Authors: Wesson Robert L. , Perkins David M. , Luco Nicolas , Karaca Erdem
Published: August 2009

We demonstrate a direct method for the calculation of the annual frequency of exceedance for earthquake losses (or the probability distribution for annual losses) to a portfolio. This method parallels the classic method of probabilistic seismic hazard analysis for the calculation of the annual frequency of exceedance for earthquake ground motions. The method assumes conditional independence of the random component of ground motions and losses at different sites for each earthquake, given magnitude, distance to the sites, and so-called interevent epsilon. Examples show that the method is realizable, and can take into account different loss functions and site conditions in the portfolio. The main advantage of this method is that it does not require a separate set of scenario earthquakes, as do Monte Carlo-based approaches, but can be calculated directly from the inputs used for hazard maps.