bluuebunny/crossref_metadata_2025 huggingface dataset:
Equine Multiple Congenital Ocular Anomalies maps to a 4.9 megabase interval on horse chromosome 6
Authors: Andersson Lisa S , Juras Rytis , Ramsey David T , Eason-Butler Jessica , Ewart Susan , Cothran Gus , Lindgren Gabriella
Published: March 2009

Background

Equine Multiple Congenital Ocular Anomalies (MCOA) syndrome consists of a diverse set of abnormalities predominantly localized to the frontal part of the eye. The disease is in agreement with a codominant mode of inheritance in our horse material. Animals presumed to be heterozygous for the mutant allele have cysts originating from the temporal ciliary body, peripheral retina and/or iris. In contrast, animals predicted to be homozygous for the disease-causing allele possess a wide range of multiple abnormalities, including iridociliary and/or peripheral retinal cysts, iridocorneal angle abnormalities, cornea globosa, iris hypoplasia and congenital cataracts. MCOA is most common in the Rocky Mountain horse breed where it occurs at a high frequency among Silver colored horses. The Silver coat color is associated with mutations inPMEL17that resides on ECA6q23. To map theMCOAlocus we analyzed 11 genetic markers on ECA6q and herein describe a chromosome interval for theMCOAlocus.

Results

We performed linkage analysis within 17 paternal half-sib families of the Rocky Mountain horse breed. More than half of the 131 offspring had the Cyst phenotype and about one third had MCOA. Segregation data were obtained by genotyping 10 microsatellite markers most of which are positioned on ECA6q22-23, as well as the missense mutation for the Silver phenotype inPMEL17. Significant linkage was found between theMCOAlocus and eight of the genetic markers, where markerUPP5(Theta = 0, z = 12.3),PMEL17ex11(Theta = 0, z = 19.0) andUPP6(Theta = 0, z = 17.5) showed complete linkage with theMCOAlocus. DNA sequencing ofPMEL17in affected and healthy control individuals did not reveal any additional mutations than the two mutations associated with the Silver coat color.

Conclusion

TheMCOAlocus can with high confidence be positioned within a 4.9 megabase (Mb) interval on ECA6q. The genotype data onUPP5,PMEL17ex11andUPP6strongly support the hypothesis that horses with the Cyst phenotype are heterozygous for the mutant allele and that horses with the MCOA phenotype are homozygous for the mutant allele.
Performance of the Genotype® MTBDRPlus resistance patternSamara, Russian Federation
Authors: Nikolayevskyy Vladyslav , Balabanova Yanina , Simak Tatyana , Malomanova Nadezhda , Fedorin Ivan , Drobniewski Francis
Published: March 2009

Background

Russia is a high tuberculosis (TB) burden country with a high prevalence of multidrug resistant tuberculosis (MDRTB). Molecular assays for detection of MDRTB on clinical specimens are not widely available in Russia.

Results

We performed an evaluation of the GenoType® MTBDRplus assay (HAIN Lifescience GmbH, Germany) on a total of 168 sputum specimens from individual patients at a public health laboratory in Central Russia, as a model of a middle income site in a region with high levels of drug resistance. Phenotypic drug resistance tests (DST) were performed on cultures derived from the same sputum specimens using the BACTEC 960 liquid media system.

Interpretable GenoType® MTBDRplus results were obtained for 154(91.7%) specimens with readability rates significantly higher in sputum specimens graded 2+ and 3+ compared to 1+ (RR = 1.17 95%CI 1.04–1.32). The sensitivity and specificity of the assay for the detection of rifampicin (RIF) and isoniazid (INH) resistance and MDR was 96.2%, 97.4%, 97.1% and 90.7%, 83.3%, 88.9% respectively. Mutations in codon 531 of the rpoB gene and codon 315 of the katG gene dominated in RIF and INH resistant strains respectively. Disagreements between phenotypical and molecular tests results (12 samples) could be explained by the presence of rare mutations in strains circulating in Russia and simultaneous presence of resistant and sensitive bacilli in sputum specimens (heteroresistance).

Conclusion

High sensitivity, short turnaround times and the potential for screening large numbers of specimens rapidly, make the GenoType® MTBDRplus assay suitable as a first-line screening assay for drug resistant TB.
Verification of the ProPneumo-1 assay for the simultaneous detection of Mycoplasma pneumoniae and Chlamydophila pneumoniae in clinical respiratory specimens
Authors: Higgins Rachel R , Lombos Ernesto , Tang Patrick , Rohoman Karl , Maki Anne , Brown Shirley , Jamieson Frances , Drews Steven J
Published: March 2009

Background

Mycoplasma pneumoniae and Chlamydophila pneumoniae are major causes of lower and upper respiratory infections that are difficult to diagnose using conventional methods such as culture. The ProPneumo-1 (Prodesse, Waukesha, WI) assay is a commercial multiplex real-time PCR assay for the simultaneous detection of M. pneumoniae and/or C. pneumoniae DNA in clinical respiratory samples.

Objective

The aim of this study was to evaluate the sensitivity and specificity of the ProPneumo-1, a newly developed commercial multiplex real-time PCR assay.

Methods

A total of 146 clinical respiratory specimens, collected from 1997 to 2007, suspected of C. pneumoniae or M. pneumoniae infections were tested retrospectively. Nucleic acid was extracted using an automated NucliSense easyMag (bioMerieux, Netherlands). We used a "Home-brew" monoplex real-time assay as the reference method for the analysis of C. pneumoniae and culture as the reference method for the analysis of M. pneumoniae. For discordant analysis specimens were re-tested using another commercial multiplex PCR, the PneumoBacter-1 assay (Seegene, Korea).

Results

Following discordant analysis, the sensitivity of the ProPneumo-1 assay for pathogens, C. pneumoniae or M. pneumoniae, was 100%. The specificity of the ProPneumo-1 assay, however, was 100% for C. pneumoniae and 98% for M. pneumoniae. The limits of detection were 1 genome equivalent (Geq) per reaction for pathogens, M. pneumoniae and C. pneumoniae. Due to the multipex format of the ProPneumo-1 assay, we identified 5 additional positive specimens, 2 C. pneumoniae in the M. pneumoniae-negative pool and 3 M. pneumoniae in the C. pneumoniae-negative pool.

Conclusion

The ProPneumo-1 assay is a rapid, sensitive and effective method for the simultaneous detection of M. pneumoniae and C. pneumoniae directly in respiratory specimens.
Inhibition of p38 MAP kinase pathway induces apoptosis and prevents Epstein Barr virus reactivation in Raji cells exposed to lytic cycle inducing compounds
Authors: Matusali Giulia , Arena Giuseppe , De Leo Alessandra , Di Renzo Livia , Mattia Elena
Published: March 2009

Background

EBV lytic cycle activators, such as phorbol esters, anti-immunoglobulin, transforming growth factor β (TGFβ), sodium butyrate, induce apoptosis in EBV-negative but not in EBV-positive Burkitt's lymphoma (BL) cells. To investigate the molecular mechanisms allowing EBV-infected cells to be protected, we examined the expression of viral and cellular antiapoptotic proteins as well as the activation of signal transduction pathways in BL-derived Raji cells exposed to lytic cycle inducing agents.

Results

Our data show that, following EBV activation, the latent membrane protein 1 (LMP1) and the cellular anti-apoptotic proteins MCL-1 and BCL-2 were quickly up-regulated and that Raji cells remained viable even when exposed simultaneously to P(BU)2, sodium butyrate and TGFβ. We report here that inhibition of p38 pathway, during EBV activation, led to a three fold increment of apoptosis and largely prevented lytic gene expression.

Conclusion

These findings indicate that, during the switch from the latent to the lytic phase of EBV infection, p38 MAPK phosphorylation plays a key role both for protecting the host cells from apoptosis as well as for inducing viral reactivation. Because Raji cells are defective for late antigens expression, we hypothesize that the increment of LMP1 gene expression in the early phases of EBV lytic cycle might contribute to the survival of the EBV-positive cells.
Anti-inflammatory effects of the gorgonian Pseudopterogorgia elisabethae collected at the Islands of Providencia and San Andrés (SW Caribbean)
Authors: Correa Hebelin , Valenzuela Alba Lucia , Ospina Luis Fernando , Duque Carmenza
Published: March 2009

Background

We are reporting for the first time the in vivo anti-inflammatory activity of extracts and fractions, and in vitro anti-inflammatory activity of pure compounds, all isolated from Pseudopterogorgia elisabethae collected at the Providencia (chemotype 1) and San Andrés (chemotype 2) Islands (SW Caribbean).

Methods

Extracts from P. elisabethae were fractionated on silica gel to yield fractions: F-1 (pseudopterosins PsQ, PsS and PsU) and F-2 (amphilectosins A and B, PsG, PsK, PsP and PsT and seco-pseudopterosins seco-PsJ and seco-PsK) from chemotype 1, and F-3 (elisabethatrienol, 10-acetoxy-9-hydroxy- and 9-acetoxy-10-hydroxy-amphilecta-8,10,12,14-tetraenes (interconverting mixture) and amphilecta-8(13),11,14-triene-9,10-dione) from chemotype 2. By using preparative RP-HPLC and spectroscopic means, we obtained the pure PsG, PsK, PsP, PsQ, PsS, PsT, PsU, seco-PsK and the interconverting mixture of non-glycosylated diterpenes (IMNGD). The anti-inflammatory properties of extracts and fractions were evaluated using in vivo model "12-O-tetradecanoyl-phorbol-acetate (TPA)-induced mouse ear oedema". The activities of pure compounds and of the IMNGD were evaluated using in vitro assays myeloperoxidase (MPO) release (by human polymorphonuclear neutrophils (PMNs)), nitric oxide release (by J-774 cells) and scavenger activity on NO.

Results

In the in vivo anti-inflammatory assay, extracts and F-3 showed low inhibition levels of inflammation compared to indomethacin, F-1 and F-2. Additionally, we evaluated the MPO release to the inflammation site, and found a marked inhibition of MPO levels by all extracts and fractions, even superior to the inhibition shown by indomethacin.

Furthermore, in the MPO in vitro assay, IMNGD, PsQ, PsS, PsT and PsU, exhibited higher inhibition levels compared to dexamethasone and indomethacin. In the NO release in vitro, IMNGD, PsP and PsT were the most potent treatments. Finally, because the PsG, PsP and seco-PsK did not exhibit any NO scavenger activity, they should inhibit the inducible Nitric Oxide Synthase (iNOS) or other routes that influence this enzyme. Alternatively, PsQ, PsS, and PsU did show scavenger activity.

Conclusion

All results presented contribute to demonstrate that the compounds isolated in this work from P. elisabethae are promising molecules with an interesting anti-inflammatory activity profile. Additionally, the results obtained could provide preliminary insights towards their structure-activity relationship.
Outcomes of resection and non-resection strategies in management of patients with advanced colorectal cancer
Authors: Evans Martyn D , Escofet Xavier , Karandikar Sharad S , Stamatakis Jeffrey D
Published: March 2009

Background

The management of patients with surgically incurable bowel cancer at presentation is controversial. The aims of treatment are to optimise quality of life and prolong survival. It has been believed that the most effective palliation is achieved by resection of the primary cancer in order to pre-empt future complications. This study reviews and compares the outcomes of patients with incurable bowel cancer managed by resection and non-resection strategies over a 7-year period in a single District General Hospital.

Patients and methods

All patients with surgically incurable bowel cancer at presentation were identified from the prospectively collected local ACPGBI database. Survival, using Kaplan-Meier method and log-rank test, was compared between patients managed by resection of the primary, non-resectional intervention (surgery, stent & oncological treatments) and those managed with supportive care only. The primary endpoint of the study was survival on an intention to treat basis, compared using Kaplan-Meier and log-rank tests.

Results

Of 646 consecutive newly diagnosed bowel cancer patients over a 7 year period 154 cases (24%) were deemed surgically incurable at presentation. Of these surgical resection was carried out in 45 patients (29%), non-resectional intervention was followed in 52 patients (34%) and supportive treatment alone in 57 patients (37%). Median survival of each group was as follows: resected patients 11 months (I.Q range 3–18 months), non-resectional intervention 7 months (I.Q range 2–15 months) and supportive care alone 2 months (I.Q range 1–8 months). Only one patient (2%) managed by non-resectional intervention required later surgery to treat primary tumour related complications. Survival was not significantly different between resection and non-resection treatments. The overall operative mortality for the resection group was 16% (7/45 cases), with an elective mortality of 14% (4/28 cases) and emergency mortality 18% (3/17 cases).

Conclusion

In an unselected bowel cancer population surgical resection of the primary tumour in patients presenting with incurable disease does not improve survival and is associated with a high risk of post-operative mortality.
The Spanish HIV BioBank: a model of cooperative HIV research
Authors: García-Merino Isabel , de las Cuevas Natividad , Jiménez José Luis , Gallego Jorge , Gómez Coral , Prieto Cristina , Serramía Ma Jesús , Lorente Raquel , Muñoz-Fernández Ma Ángeles ,   Spanish HIV BioBank
Published: March 2009

Background

The collection of samples from HIV-infected patients is the beginning of the chain of translational research. To carry out quality research that could eventually end in a personalized treatment for HIV, it is essential to guarantee the availability, quality and traceability of samples, under a strict system of quality management.

Methods

The Spanish HIV BioBank was created with the objectives of processing, storing and providing distinct samples from HIV/AIDS patients, categorized according to strictly defined characteristics, free of charge to research projects. Strict compliance to ethical norms is always guaranteed.

Results

At the moment, the HIV BioBank possesses nearly 50,000 vials containing different prospective longitudinal study sample types. More than 1,700 of these samples are now used in 19 national and international research projects.

Conclusion

The HIV BioBank represents a novel approach to HIV research that might be of general interest not only for basic and clinical research teams working on HIV, but also for those groups trying to establish large networks focused on research on specific clinical problems. It also represents a model to stimulate cooperative research among large numbers of research groups working as a network on specific clinical problems. The main objective of this article is to show the structure and function of the HIV BioBank that allow it to very efficiently release samples to different research project not only in Spain but also in other countries.
Gz Mediates the Long-Lasting Desensitization of Brain CB1 Receptors and is Essential for Cross-Tolerance with Morphine
Authors: Garzón Javier , de la Torre-Madrid Elena , Rodríguez-Muñoz María , Vicente-Sánchez Ana , Sánchez-Blázquez Pilar
Published: March 2009

Background

Although the systemic administration of cannabinoids produces antinociception, their chronic use leads to analgesic tolerance as well as cross-tolerance to morphine. These effects are mediated by cannabinoids binding to peripheral, spinal and supraspinal CB1 and CB2 receptors, making it difficult to determine the relevance of each receptor type to these phenomena. However, in the brain, the CB1 receptors (CB1Rs) are expressed at high levels in neurons, whereas the expression of CB2Rs is marginal. Thus, CB1Rs mediate the effects of smoked cannabis and are also implicated in emotional behaviors. We have analyzed the production of supraspinal analgesia and the development of tolerance at CB1Rs by the direct injection of a series of cannabinoids into the brain. The influence of the activation of CB1Rs on supraspinal analgesia evoked by morphine was also evaluated.

Results

Intracerebroventricular (icv) administration of cannabinoid receptor agonists, WIN55,212-2, ACEA or methanandamide, generated a dose-dependent analgesia. Notably, a single administration of these compounds brought about profound analgesic tolerance that lasted for more than 14 days. This decrease in the effect of cannabinoid receptor agonists was not mediated by depletion of CB1Rs or the loss of regulated G proteins, but, nevertheless, it was accompanied by reduced morphine analgesia. On the other hand, acute morphine administration produced tolerance that lasted only 3 days and did not affect the CB1R. We found that both neural mu-opioid receptors (MORs) and CB1Rs interact with the HINT1-RGSZ module, thereby regulating pertussis toxin-insensitive Gz proteins. In mice with reduced levels of these Gz proteins, the CB1R agonists produced no such desensitization or morphine cross-tolerance. On the other hand, experimental enhancement of Gz signaling enabled an acute icv administration of morphine to produce a long-lasting tolerance at MORs that persisted for more than 2 weeks, and it also impaired the analgesic effects of cannabinoids.

Conclusion

In the brain, cannabinoids can produce analgesic tolerance that is not associated with the loss of surface CB1Rs or their uncoupling from regulated transduction. Neural specific Gz proteins are essential mediators of the analgesic effects of supraspinal CB1R agonists and morphine. These Gz proteins are also responsible for the long-term analgesic tolerance produced by single doses of these agonists, as well as for the cross-tolerance between CB1Rs and MORs.
Small molecule activators of SIRT1 replicate signaling pathways triggered by calorie restriction in vivo
Authors: Smith Jesse J , Kenney Renée Deehan , Gagne David J , Frushour Brian P , Ladd William , Galonek Heidi L , Israelian Kristine , Song Jeffrey , Razvadauskaite Giedre , Lynch Amy V , Carney David P , Johnson Robin J , Lavu Siva , Iffland Andre , Elliott Peter J , Lambert Philip D , Elliston Keith O , Jirousek Michael R , Milne Jill C , Boss Olivier
Published: March 2009

Background

Calorie restriction (CR) produces a number of health benefits and ameliorates diseases of aging such as type 2 diabetes. The components of the pathways downstream of CR may provide intervention points for developing therapeutics for treating diseases of aging. The NAD+-dependent protein deacetylase SIRT1 has been implicated as one of the key downstream regulators of CR in yeast, rodents, and humans. Small molecule activators of SIRT1 have been identified that exhibit efficacy in animal models of diseases typically associated with aging including type 2 diabetes. To identify molecular processes induced in the liver of mice treated with two structurally distinct SIRT1 activators, SIRT501 (formulated resveratrol) and SRT1720, for three days, we utilized a systems biology approach and applied Causal Network Modeling (CNM) on gene expression data to elucidate downstream effects of SIRT1 activation.

Results

Here we demonstrate that SIRT1 activators recapitulate many of the molecular events downstream of CR in vivo, such as enhancing mitochondrial biogenesis, improving metabolic signaling pathways, and blunting pro-inflammatory pathways in mice fed a high fat, high calorie diet.

Conclusion

CNM of gene expression data from mice treated with SRT501 or SRT1720 in combination with supporting in vitro and in vivo data demonstrates that SRT501 and SRT1720 produce a signaling profile that mirrors CR, improves glucose and insulin homeostasis, and acts via SIRT1 activation in vivo. Taken together these results are encouraging regarding the use of small molecule activators of SIRT1 for therapeutic intervention into type 2 diabetes, a strategy which is currently being investigated in multiple clinical trials.
Impact of sample acquisition and linear amplification on gene expression profiling of lung adenocarcinoma: laser capture micro-dissection cell-sampling versus bulk tissue-sampling
Authors: Klee Eric W , Erdogan Sibel , Tillmans Lori , Kosari Farhad , Sun Zhifu , Wigle Dennis A , Yang Ping , Aubry Marie C , Vasmatzis George
Published: March 2009

Background

The methods used for sample selection and processing can have a strong influence on the expression values obtained through microarray profiling. Laser capture microdissection (LCM) provides higher specificity in the selection of target cells compared to traditional bulk tissue selection methods, but at an increased processing cost. The benefit gained from the higher tissue specificity realized through LCM sampling is evaluated in this study through a comparison of microarray expression profiles obtained from same-samples using bulk and LCM processing.

Methods

Expression data from ten lung adenocarcinoma samples and six adjacent normal samples were acquired using LCM and bulk sampling methods. Expression values were evaluated for correlation between sample processing methods, as well as for bias introduced by the additional linear amplification required for LCM sample profiling.

Results

The direct comparison of expression values obtained from the bulk and LCM sampled datasets reveals a large number of probesets with significantly varied expression. Many of these variations were shown to be related to bias arising from the process of linear amplification, which is required for LCM sample preparation. A comparison of differentially expressed genes (cancer vs. normal) selected in the bulk and LCM datasets also showed substantial differences. There were more than twice as many down-regulated probesets identified in the LCM data than identified in the bulk data. Controlling for the previously identified amplification bias did not have a substantial impact on the differences identified in the differentially expressed probesets found in the bulk and LCM samples.

Conclusion

LCM-coupled microarray expression profiling was shown to uniquely identify a large number of differentially expressed probesets not otherwise found using bulk tissue sampling. The information gain realized from the LCM sampling was limited to differential analysis, as the absolute expression values obtained for some probesets using this study's protocol were biased during the second round of amplification. Consequently, LCM may enable investigators to obtain additional information in microarray studies not easily found using bulk tissue samples, but it is of critical importance that potential amplification biases are controlled for.
Candidate autoantigens identified by mass spectrometry in early rheumatoid arthritis are chaperones and citrullinated glycolytic enzymes
Authors: Goëb Vincent , Thomas-L'Otellier Marlène , Daveau Romain , Charlionet Roland , Fardellone Patrice , Le Loët Xavier , Tron François , Gilbert Danièle , Vittecoq Olivier
Published: March 2009

Introduction

The aim of our study was to identify new early rheumatoid arthritis (RA) autoantibodies.

Methods

Sera obtained from 110 early untreated RA patients (<6 months) were analyzed by western blot using HL-60 cell extract, separated on one-dimensional and two-dimensional gel electrophoresis (1-DE, 2-DE). Sera from 50 healthy blood donors and 20 patients with non-RA rheumatisms were used as controls for 1-DE and 2-DE, respectively. The immunoreactive proteins were identified by MALDI-TOF mass spectrometric analysis and the presence of potential sites of citrullination in each of these proteins was evaluated. FT-ICR mass spectrometry was used to verify experimentally the effect of citrullination upon the mass profile observed by MALDI-TOF analysis.

Results

The 110 1-DE patterns allowed detection of 10 recurrent immunoreactive bands of 33, 39, 43, 46, 51, 54, 58, 62, 67 and 70 kDa, which were further characterized by 2-DE and proteomic analysis. Six proteins were already described RA antigens: heterogeneous nuclear ribonucleoprotein A2/B1, aldolase, α-enolase, calreticulin, 60 kDa heat shock protein (HSP60) and BiP. Phosphoglycerate kinase 1 (PGK1), stress-induced phosphoprotein 1 and the far upstream element-binding proteins (FUSE-BP) 1 and 2 were identified as new antigens. Post-translational protein modifications were analyzed and potentially deiminated peptides were found on aldolase, α-enolase, PGK1, calreticulin, HSP60 and the FUSE-BPs. We compared the reactivity of RA sera with citrullinated and noncitrullinated α-enolase and FUSE-BP linear peptides, and showed that antigenicity of the FUSE-BP peptide was highly dependent on citrullination. Interestingly, the anti-cyclic citrullinated peptide antibody (anti-CCP2) status in RA serum at inclusion was not correlated to the reactivity directed against FUSE-BP citrullinated peptide.

Conclusions

Two categories of antigens, enzymes of the glycolytic family and molecular chaperones are also targeted by the early untreated RA autoantibody response. For some of them, and notably the FUSE-BPs, citrullination is involved in the immunological tolerance breakdown observed earlier in RA patients. Autoantibodies recognizing a citrullinated peptide from FUSE-BP may enhance the sensibility for RA of the currently available anti-CCP2 test.
T-cell metagene predicts a favorable prognosis in estrogen receptor-negative and HER2-positive breast cancers
Authors: Rody Achim , Holtrich Uwe , Pusztai Laos , Liedtke Cornelia , Gaetje Regine , Ruckhaeberle Eugen , Solbach Christine , Hanker Lars , Ahr Andre , Metzler Dirk , Engels Knut , Karn Thomas , Kaufmann Manfred
Published: March 2009

Introduction

Lymphocyte infiltration (LI) is often seen in breast cancer but its importance remains controversial. A positive correlation of human epidermal growth factor receptor 2 (HER2) amplification and LI has been described, which was associated with a more favorable outcome. However, specific lymphocytes might also promote tumor progression by shifting the cytokine milieu in the tumor.

Methods

Affymetrix HG-U133A microarray data of 1,781 primary breast cancer samples from 12 datasets were included. The correlation of immune system-related metagenes with different immune cells, clinical parameters, and survival was analyzed.

Results

A large cluster of nearly 600 genes with functions in immune cells was consistently obtained in all datasets. Seven robust metagenes from this cluster can act as surrogate markers for the amount of different immune cell types in the breast cancer sample. An IgG metagene as a marker for B cells had no significant prognostic value. In contrast, a strong positive prognostic value for the T-cell surrogate marker (lymphocyte-specific kinase (LCK) metagene) was observed among all estrogen receptor (ER)-negative tumors and those ER-positive tumors with a HER2 overexpression. Moreover ER-negative tumors with high expression of both IgG and LCK metagenes seem to respond better to neoadjuvant chemotherapy.

Conclusions

Precise definitions of the specific subtypes of immune cells in the tumor can be accomplished from microarray data. These surrogate markers define subgroups of tumors with different prognosis. Importantly, all known prognostic gene signatures uniformly assign poor prognosis to all ER-negative tumors. In contrast, the LCK metagene actually separates the ER-negative group into better or worse prognosis.
Uncovering metabolic pathways relevant to phenotypic traits of microbial genomes
Authors: Kastenmüller Gabi , Schenk Maria Elisabeth , Gasteiger Johann , Mewes Hans-Werner
Published: March 2009

Identifying the biochemical basis of microbial phenotypes is a main objective of comparative genomics. Here we present a novel method using multivariate machine learning techniques for comparing automatically derived metabolic reconstructions of sequenced genomes on a large scale. Applying our method to 266 genomes directly led to testable hypotheses such as the link between the potential of microorganisms to cause periodontal disease and their ability to degrade histidine, a link also supported by clinical studies.
Prospective, Multicenter, Randomized Trial of a New Organizational Modality for Providing Information and Support to Cancer Patients
Authors: Passalacqua Rodolfo , Caminiti Caterina , Campione Francesco , Diodati Francesca , Todeschini Renata , Bisagni Giancarlo , Labianca Roberto , Dalla Chiesa Matteo , Bracci Raffaella , Aragona Marcello , Artioli Fabrizio , Cavanna Luigi , Masina Alceste , De Falco Francesco , Marzocchini Barbara , Iacono Carmelo , Contu Antonio , Di Costanzo Francesco , Bertetto Oscar , Annunziata Maria A.
Published: March 2009

Purpose

No structured modality for providing information and support to patients in oncology wards has been validated in clinical trials.

Methods

This is a pragmatic, two-arm, cluster randomized trial, with the oncology ward as random assignment unit. Centers were allocated to implement a Point of Information and Support (PIS) or to a control group. The PIS included a library for cancer patients and a specifically trained oncology nurse. End points, measured at patient level, were psychological distress and satisfaction with received information. Both intent-to-treat and per-protocol analyses considering clustering were performed.

Results

Thirty-eight Italian cancer centers were randomly assigned, and 6 months after PIS creation, 3,286 unselected, consecutive cancer patients were surveyed (1,654 in the experimental group and 1,632 in the control group). Three thousand one hundred ninety-seven (97%) questionnaires were collected and deemed valid. Fifty-two percent of centers (11 of 21 centers) in the experimental arm did not implement the PIS in accordance with the protocol. Overall, 34% of patients showed moderate to severe psychological distress, and only 9% declared dissatisfaction. Intent-to-treat analysis did not yield significant differences. Although the per-protocol analysis did show a reduction in psychological distress (28.9% for functioning PIS v 33.3% for no PIS) and dissatisfaction (6.4% for functioning PIS v 9.3% for no PIS), differences did not reach significance.

Conclusion

This is the first cluster randomized trial aiming to demonstrate that a structured modality of providing information reduces psychological distress. We did not find this, but we believe results should be interpreted cautiously, particularly because of the low compliance with PIS implementation. Context analysis preceding such interventions is essential.
Meta-Analysis of Single-Agent Chemotherapy Compared With Combination Chemotherapy As Second-Line Treatment of Advanced Non–Small-Cell Lung Cancer
Authors: Di Maio Massimo , Chiodini Paolo , Georgoulias Vassilis , Hatzidaki Dora , Takeda Koji , Wachters Floris M. , Gebbia Vittorio , Smit Egbert F. , Morabito Alessandro , Gallo Ciro , Perrone Francesco , Gridelli Cesare
Published: March 2009

Purpose

Doublet chemotherapy is more effective than single-agent as first-line treatment of advanced non–small-cell lung cancer (NSCLC). As second-line treatment, several randomized trials have been performed comparing single-agent with doublet chemotherapy, but each trial had an insufficient power to detect potentially relevant differences in survival.

Methods

We performed meta-analysis of individual patient data from randomized trials, both published and unpublished, comparing single-agent with doublet chemotherapy as second-line treatment of advanced NSCLC. Primary end point was overall survival (OS). All statistical analyses were stratified by trial.

Results

Eight eligible trials were identified. Data of two trials were not available, and data of six trials (847 patients) were collected. Median age was 61 years. Performance status was 0 or 1 in 90%; 80% of patients had received previous platin-based chemotherapy. OS was not significantly different between arms (P = .32). Median OS was 37.3 and 34.7 weeks in the doublet and single-agent arms, respectively. Hazard ratio (HR) was 0.92 (95% CI, 0.79 to 1.08). Response rate was 15.1% with doublet and 7.3% with single-agent (P = .0004). Median progression-free survival was 14 weeks for doublet and 11.7 weeks for single agent (P = .0009; HR, 0.79; 95% CI, 0.68 to 0.91). There was no significant heterogeneity among trials for the three efficacy outcomes. Patients treated with doublet chemotherapy had significantly more grade 3 to 4 hematologic (41% v 25%; P < .0001) and grade 3 to 4 nonhematologic toxicity (28% v 22%; P = .034).

Conclusion

Doublet chemotherapy as second-line treatment of advanced NSCLC significantly increases response rate and progression-free survival, but is more toxic and does not improve overall survival compared to single-agent.
Microsatellite Instability Predicts Improved Response to Adjuvant Therapy With Irinotecan, Fluorouracil, and Leucovorin in Stage III Colon Cancer: Cancer and Leukemia Group B Protocol 89803
Authors: Bertagnolli Monica M. , Niedzwiecki Donna , Compton Carolyn C. , Hahn Hejin P. , Hall Margaret , Damas Beatrice , Jewell Scott D. , Mayer Robert J. , Goldberg Richard M. , Saltz Leonard B. , Warren Robert S. , Redston Mark
Published: March 2009

Purpose

Colon cancers exhibiting DNA mismatch repair (MMR) defects demonstrate distinct clinical and pathologic features, including better prognosis and reduced response to fluorouracil (FU) –based chemotherapy. This prospective study investigated adjuvant chemotherapy containing FU and irinotecan in patients with MMR deficient (MMR-D) colon cancers.

Patients and Methods

Cancer and Leukemia Group B 89803 randomly assigned 1,264 patients with stage III colon cancer to postoperative weekly bolus FU/leucovorin (LV) or weekly bolus irinotecan, FU, and LV (IFL). The primary end point was overall survival; disease-free survival (DFS) was a secondary end point. Tumor expression of the MMR proteins, MLH1 and MSH2, was determined by immunohistochemistry (IHC). DNA microsatellite instability was also assessed using a panel of mono- and dinucleotide markers. Tumors with MMR defects were those demonstrating loss of MMR protein expression (MMR-D) and/or microsatellite instability high (MSI-H) genotype.

Results

Of 723 tumor cases examined by genotyping and IHC, 96 (13.3%) were MMR-D/MSI-H. Genotyping results were consistent with IHC in 702 cases (97.1%). IFL-treated patients with MMR-D/MSI-H tumors showed improved 5-year DFS as compared with those with mismatch repair intact tumors (0.76; 95% CI, 0.64 to 0.88 v 0.59; 95% CI, 0.53 to 0.64; P = .03). This relationship was not observed among patients treated with FU/LV. A trend toward longer DFS was observed in IFL-treated patients with MMR-D/MSI-H tumors as compared with those receiving FU/LV (0.57; 95% CI, 0.42 to 0.71 v 0.76; 95% CI, 0.64 to 0.88; P = .07; hazard ratio interaction between tumor status and treatment, 0.51; likelihood ratio P = .117).

Conclusion

Loss of tumor MMR function may predict improved outcome in patients treated with the IFL regimen as compared with those receiving FU/LV.
Adjuvant Therapy With the Monoclonal Antibody Edrecolomab Plus Fluorouracil-Based Therapy Does Not Improve Overall Survival of Patients With Stage III Colon Cancer
Authors: Fields Anthony L.A. , Keller Alan , Schwartzberg Lee , Bernard Stephen , Kardinal Carl , Cohen Alan , Schulz Joe , Eisenberg Peter , Forster John , Wissel Paul
Published: March 2009

Purpose

Edrecolomab (ED) is a murine monoclonal antibody targeting the EpCam antigen. This phase III randomized multicenter trial investigated the benefit of adding ED to fluorouracil (FU) based therapy in patients with stage III colorectal cancer.

Patients and Methods

Patients with stage III colon cancer were randomly assigned to one of two treatments after curative surgery. Patients in arm 1 received five infusions of ED together with FU-based chemotherapy; patients in arm 2 received FU-based chemotherapy alone. The primary end point was overall survival (OS).

Results

One thousand eight hundred thirty-nine patients were randomly assigned; results were analyzed on an intent-to-treat basis. Patient characteristics were well-balanced across treatment arms. Five-year follow-up has been completed. Patients randomly assigned to ED plus FU-based therapy showed a 5-year survival rate of 69.6% while for patients receiving FU-based therapy, the rate was 68.2%. The hazard ratio for death with ED plus FU-based therapy compared to FU-based therapy was 0.896 (95% CI, 0.752 to 1.068), which was not statistically significant (P = .220). The adverse effect profiles of the two treatment arms were similar, with the main adverse effects being diarrhea, abdominal pain, and nausea. Anaphylaxis occurred in fewer than 1% of patients receiving ED.

Conclusion

For patients with stage III colon cancer, the addition of ED to FU-based therapy had no statistically significant effect on OS.
Diagnostic Assay Based on hsa-miR-205 Expression Distinguishes Squamous From Nonsquamous Non–Small-Cell Lung Carcinoma
Authors: Lebanony Danit , Benjamin Hila , Gilad Shlomit , Ezagouri Meital , Dov Avital , Ashkenazi Karin , Gefen Nir , Izraeli Shai , Rechavi Gideon , Pass Harvey , Nonaka Daisuke , Li Junjie , Spector Yael , Rosenfeld Nitzan , Chajut Ayelet , Cohen Dalia , Aharonov Ranit , Mansukhani Mahesh
Published: March 2009

Purpose

Recent advances in treatment of lung cancer require greater accuracy in the subclassification of non–small-cell lung cancer (NSCLC). Targeted therapies which inhibit tumor angiogenesis pose higher risk for adverse response in cases of squamous cell carcinoma. Interobserver variability and the lack of specific, standardized assays limit the current abilities to adequately stratify patients for such treatments. In this study, we set out to identify specific microRNA biomarkers for the identification of squamous cell carcinoma, and to use such markers for the development of a standardized assay.

Patients and Methods

High-throughput microarray was used to measure microRNA expression levels in 122 adenocarcinoma and squamous NSCLC samples. A quantitative real-time polymerase chain reaction (qRT-PCR) platform was used to verify findings in an independent set of 20 NSCLC formalin-fixed, paraffin-embedded (FFPE) samples, and to develop a diagnostic assay using an additional set of 27 NSCLC FFPE samples. The assay was validated using an independent blinded cohort consisting of 79 NSCLC FFPE samples.

Results

We identified hsa-miR-205 as a highly specific marker for squamous cell lung carcinoma. A microRNA-based qRT-PCR assay that measures expression of hsa-miR-205 reached sensitivity of 96% and specificity of 90% in the identification of squamous cell lung carcinomas in an independent blinded validation set.

Conclusion

Hsa-miR-205 is a highly accurate marker for lung cancer of squamous histology. The standardized diagnostic assay presented here can provide highly accurate subclassification of NSCLC patients.
Randomized Phase II Trial Evaluating Two Paclitaxel and Cisplatin–Containing Chemoradiation Regimens As Adjuvant Therapy in Resected Gastric Cancer (RTOG-0114)
Authors: Schwartz Gary K. , Winter Kathryn , Minsky Bruce D. , Crane Christopher , Thomson P. John , Anne Pramila , Gross Howard , Willett Christopher , Kelsen David
Published: March 2009

Purpose

The investigational arm of INT0116, a fluorouracil (FU) and leucovorin–containing chemoradiotherapy regimen, is a standard treatment for patients with resected gastric cancer with a 2-year disease-free survival rate (DFS) of 52%. Toxicity is also significant. More beneficial and safer regimens are needed.

Patients and Methods

We performed a randomized phase II study among 39 cancer centers to evaluate two paclitaxel and cisplatin–containing regimens, one with FU (PCF) and the other without (PC) in patients with resected gastric cancer. Patients received two cycles of postoperative chemotherapy followed by 45 Gy of radiation with either concurrent FU and paclitaxel or paclitaxel and cisplatin. The primary objective was to show an improvement in 2-year DFS to 67% as compared with INT 0116.

Results

From May 2001 to February 2004 (study closure), 78 patients entered this study, and 73 were evaluable. At the planned interim analysis of 22 patients on PCF, grade 3 or higher GI toxicity was 59%. This was significantly worse than INT0116, and this arm was closed. Accrual continued on PC. The median DFS was 14.6 months for PCF and has not been reached for PC. For PC the 2-year DFS is 52% (95% CI, 36% to 68%).

Conclusion

Though PC appears to be safe and the median DFS favorable, the DFS failed to exceed the lower bound of 52.9% for the targeted 67% DFS at 2 years and can not be recommended as the adjuvant arm for future randomized trials.
Where's the Revolution? Digital Technology and Health Care in the Internet Age
Authors: Miller Edward Alan , West Darrell M.
Published: March 2009

Despite the growing use of online resources, it is unclear how many Americans are using the World Wide Web for different health-related purposes and whether factors promoting use of the Internet in health care correspond with those affecting more traditional in-person and telemedicine encounters. This research uses a national public opinion survey to examine the degree to which health care consumers communicate through conventional, face-to-face consultation, telemedicine, or digital technology, and the relationship between these means of communication and respondent characteristics. Results indicate that few people are using digital technology to get information, communicate with health personnel, or make online medical purchases. Furthermore, less well educated, lower-income individuals living in rural areas tend to use the health care Internet less than others. Several policy measures need to be undertaken in order to accelerate the appropriate use of digital technology by health care consumers of all kinds. These include improving education and technological literacy and providing access to low-cost digital technology. Without a consumer complement to prevailing efforts to spur health information technology development and implementation on the part of providers, the promise of the digital revolution will continue to be limited to certain better-connected segments of the population.
Film Review
Authors: Rowell Erica
Published: March 2009

Burn After Reading (2008)

Burn After Reading (2008) Directors Joel and Ethan Coen Screenplay Joel and Ethan Coen Producers Joel and Ethan Coen Director of Photography Emmanuel Lubezki Production Designer Jess Gonchor Art Director
David Swayze Costumes Mary Zophres With George Clooney (Harry Pfarrer), Frances McDormand (Linda Litzke), Brad Pitt (Chad Feldheimer), John Malkovich (Osborne Cox), Tilda Swinton (Katie Cox), Richard Jenkins (Ted), J.K. Simmons (CIA Superior) Runtime 96 minutes
Guidelines for Evaluation of the Permanence of a Stabilization/Solidification Technology
Authors: Soundararajan R
Published: March 2009

Stabilization/solidification technologies are used widely for treating both inorganic and organic waste materials. Unfortunately, some of these processes have turned out to be simple adsorption/dilution phenomena. For a true stabilization/solidification process, the binder and the waste must interact chemically to create chemical bonding. Based on our past investigations in this area, some guidelines for evaluating the permanence of a stabilization/solidification process are presented in this paper.
A Critical Review of the Effectiveness of Stabilization and Solidification of Hazardous Organic Wastes
Authors: Brown RE , Jindal BS , Bulzan JD
Published: March 2009

A critical review is presented on the stabilization/solidification (S/S) of hazardous organic wastes (WASTES). The literature on the S/S of WASTES with cementing agents containing expandable lattice clay binders modified by cation exchange with quaternary ammonium cations (MODIFIED CLAYS) suggests that hazardous organic waste constituents (ORGANICS) may form permanent chemical bonds preventing future releases of ORGANICS into the environment. This conclusion is compared with basic studies on the sorption of ORGANICS from aqueous solutions by soils and MODIFIED CLAYS. This latter literature would suggest that sorption of ORGANICS from aqueous solutions is an equilibrium process wherein the MODIFIED CLAYS buffer the concentration of ORGANICS in the equilibrium aqueous solution rather than a process forming permanent chemical bonds, thereby preventing the movement of ORGANICS into the environment. Often the buffered concentration of ORGANICS in the equilibrium aqueous solution is far in excess of drinking water standards and therefore S/S WASTES are not necessarily environmentally safe. Discussions are presented on difficulties in relating data on the sorption of ORGANICS by MODIFIED CLAYS to conclusions regarding possible retention of ORGANICS against releases to the environment. Overall considerations are then given to the practice of S/S of WASTES at treatment, storage, and disposal (TSD) facilities.
Stabilization/Solidification of Wastes Containing Volatile Organic Compounds in Commercial Cementitious Waste Forms
Authors: Spence RD , Gilliam TM , Morgan IL , Osborne SC
Published: March 2009

Stabilization/solidification (S/S) is one of the most widely used techniques for waste treatment and remedial actions, but does not have regulatory approval for treating organics. Application with volatile organic compounds (VOCs) is particularly controversial since it was believed that the necessary mechanical mixing and exothermic cementitious reactions would vaporize the VOCs. The objective of this study was to establish whether S/S is a viable alternative for a sludge heavily contaminated (about 1%) with relatively immobile metals, but lightly contaminated (<0.04%) with VOCs that were contaminating the groundwater. The mass balance indicated that >50% of the VOCs were retained in the laboratory preparation of cementitious samples cured for 28 days. The performance tests indicated the commercial products could attain leachability indices from 7 to >9 for the eight VOCs studied and distribution coefficients of > 10 could be attained for all eight and > 100 for some compounds.
Incorporation of Radioactive Ashes into Ceramic-Clay Matrices
Authors: Aloy AS , Vishnevskii AS , Kolycheva TI , Kuznetsov BS , Shashukov EA
Published: March 2009

The possibility for immobilization of ashes arising from incineration of radioactive wastes generated in research centers was investigated on a laboratory scale. Ceramic materials based on natural clays were made by routine ceramic techniques. It was shown that ceramics on the basis of Chasovyar clay may incorporate up to 30 vol% of ash and that the products obtained at 1050°C have a high chemical stability and mechanical strength. It is concluded that the proposed method deserves further study aimed at the development of process equipment.
Chemical Fixation of Flue Gas Desulfurization Sludges and Fly Ash
Authors: Bishop PL , Keener TC , Dusing DC , Gong R , Li C-L
Published: March 2009

A study is under way to investigate the heavy metal binding mechanisms in solidified/stabilized high sulfur coal fly ash and flue gas desulfurization (FGD) sludges. Fly ash and sludge from a typical wet FGD process and dry flue gas desulfurization by-product from a demonstration lime injection multistage burner (LIMB) process are being evaluated. The latter material contains substantial portions of available lime and may prove amenable as a solidifying agent with the fly ash. This paper describes initial results on the waste characterization, solidified/stabilized waste form formulation, and influence of liquid/solid ratio on metal leaching from the waste forms.