bluuebunny/crossref_metadata_2025 huggingface dataset:
Regulation of HSP27 on NF-κB pathway activation may be involved in metastatic hepatocellular carcinoma cells apoptosis
Authors: Guo Kun , Kang Nan Xiao , Li Yan , Sun Lu , Gan Lin , Cui Feng Jie , Gao Mei Dong , Liu Kun Yin
Published: March 2009

Background

During the process of metastasis, cells are subjected to various apoptotic stimuli. Aberrant expression of apoptotic regulators often contribute to cell metastasis. Heat shock protein 27(HSP27) is confirmed as an apoptosis regulator, but its antiapoptotic mechanism in metastatic hepatocellular carcinoma (HCC) cells remains unclear.

Methods

Levels of HSP27 protein and its phosphorylation in Hep3B, MHCC97L to MHCC97H cells with different metastatic potentials were determined by western blot analysis. MHCC97H cells were transfected with specific small interference RNA (siRNA) against HSP27. The in vitro migration and invasion potentials of cells were evaluated by Transwell assay. The apoptosis ratio of MHCC97H cells was analyzed by TUNEL staining and Flow Cytometry. Alteration of signal transduction pathway after HSP27 knockdown in MHCC97H cells was evaluated through a Human Q Series Signal Transduction in Cancer Gene Array analysis. Nuclear NF-κB contentration and endogenous IKK activity were demonstrated by ELISA assay. The association of IKKα, IKKβ, IκBα with HSP27 and the association between IKKβ and IKKα in MHCC97H cells were determined by co-immunoprecipitation assay followed by western blot analysis.

Results

HSP27 protein and its phosphorylation increased in parallel with enhanced metastatic potentials of HCC cells. siRNA-mediated HSP27 knockdown in MHCC97H significantly suppressed cells migration and invasion in vitro and induced cell apoptosis; the prominently altered signal transduction pathway was NF-κB pathway after HSP27 knockdown in MHCC97H cells. Furthermore, inhibition of HSP27 expression led to a significant decrease of nuclear NF-κB contentration and endogenous IKK activity. In addition, HSP27 was associated with IKKα, IKKβ, IκBα in three HCC cells above. ELISA assay and western blot analysis also showed a decrease of the association between IKKβ and IKKα, the association between phosphor-HSP27 and IKK complex, and an increase of total IκBα but reducing tendency of phosphor-IκBα when HSP27 expression was efficiently knocked down in MHCC97H cells.

Conclusion

Altogether, these findings revealed a possible effect of HSP27 on apoptosis in metastatic HCC cells, in which HSP27 may regulate NF-kB pathway activation.
Timeliness of national notifiable diseases surveillance system in Korea: a cross-sectional study
Authors: Yoo Hyo-Soon , Park Ok , Park Hye-Kyung , Lee Eun-Gyu , Jeong Eun-Kyeong , Lee Jong-Koo , Cho Sung-Il
Published: March 2009

Background

With the increase of international travels, infectious disease control is gaining a greater importance across regional borders. Adequate surveillance system function is crucial to prevent a global spread of infectious disease at the earliest stage. There have been limited reports on the characteristics of infectious disease surveillance in Asia. The authors studied the timeliness of the Korean National Notifiable Disease Surveillance System with regard to major notifiable diseases from 2001 to 2006.

Methods

Six notifiable infectious diseases reported relatively frequently were included in this study. Five diseases were selected by the criteria of reported cases > 100 per year: typhoid fever, shigellosis, mumps, scrub typhus, and hemorrhagic fever with renal syndrome. In addition, dengue fever was also included to represent an emerging disease, despite its low number of cases. The diseases were compared for the proportion notified within the recommended time limits, median time lags, and for the cumulative distribution of time lags at each surveillance step between symptom onset and date of notification to the Korea Centers for Disease Control and Prevention (KCDC).

Results

The proportion of cases reported in time was lower for disease groups with a recommended time limit of 1 day compared with 7 days (60%–70% vs. > 80%). The median time from disease onset to notification to KCDC ranged between 6 and 20 days. The median time from onset to registration at the local level ranged between 2 and 15 days. Distribution of time lags showed that main delays arose in the time from onset to diagnosis. There were variations in timeliness by disease categories and surveillance steps.

Conclusion

Time from disease onset to diagnosis generally contributed most to the delay in reporting. It is needed to promote public education and to improve clinical guidelines. Rapid reporting by doctors should be encouraged, and unification of recommended reporting time limit can be helpful. Our study also demonstrates the utility of the overall assessment of time-lag distributions for disease-specific strategies to improve surveillance.
Rates of asthma attacks in patients with previously inadequately controlled mild asthma treated in clinical practice with combination drug therapy: an exploratory post-hoc analysis
Authors: Dal Negro Robert W , Borderias Luis , Zhang Qiaoyi , Fan Tao , Sazonov Vasilisa , Guilera Magda , Taylor Stephanie D
Published: March 2009

Background

Differences could exist in the likelihood of asthma attacks in patients treated with inhaled corticosteroid (ICS), long-acting beta-agonist (LABA), and montelukast (MON) (ICS/LABA/MON) and patients treated with an inhaled corticosteroid (ICS) and montelukast (MON) (ICS/MON).

Methods

This was a post-hoc analysis of a pretest-posttest retrospective cohort study. Patients with mild persistent asthma and allergic rhinitis, who were taking an ICS either alone or in combination with a LABA, started concomitant MON treatment as part of their routine care. Rates of asthma- and allergic rhinitis-related medical resource use in the 12-months after the initial (index) MON prescription were compared in the ICS/MON and ICS/LABA/MON groups. An asthma attack was defined as an asthma-related hospitalization, ER visit, or use of an oral corticosteroid.

Results

Of the total of 344 patients, 181 (53%) received ICS/MON and 163 (47%) received ICS/LABA/MON in the post-index period for means of 10.5 and 11.4 months, respectively, (P < 0.05). Short-acting beta-agonists were used by 74.6% in the ICS/MON and 71.8% in the ICS/LABA/MON groups (P > 0.05). An asthma attack occurred in 4.4% of the ICS/MON group and 6.8% of the ICS/LABA/MON group (P > 0.05). The adjusted odds of an asthma attack in the post-index period in the ICS/LABA/MON group relative to the ICS/MON group was 1.24, 95% confidence interval 0.35–4.44.

Conclusion

In this observational study of combination drug treatment of mild persistent asthma and allergic rhinitis, no difference was observed between LABA/ICS/MON combination therapy and the ICS/MON combination without LABA use, for the rate of asthma attacks over one year.
Phenotypes and gene expression profiles of Saccharopolyspora erythraea rifampicin-resistant (rif) mutants affected in erythromycin production
Authors: Carata Elisabetta , Peano Clelia , Tredici Salvatore M , Ferrari Francesco , Talà Adelfia , Corti Giorgio , Bicciato Silvio , De Bellis Gianluca , Alifano Pietro
Published: March 2009

Background

There is evidence from previous works that bacterial secondary metabolism may be stimulated by genetic manipulation of RNA polymerase (RNAP). In this study we have used rifampicin selection as a strategy to genetically improve the erythromycin producer Saccharopolyspora erythraea.

Results

Spontaneous rifampicin-resistant (rif) mutants were isolated from the parental strain NRRL2338 and two rif mutations mapping within rpoB, S444F and Q426R, were characterized. With respect to the parental strain, S444F mutants exhibited higher respiratory performance and up to four-fold higher final erythromycin yields; in contrast, Q426R mutants were slow-growing, developmental-defective and severely impaired in erythromycin production. DNA microarray analysis demonstrated that these rif mutations deeply changed the transcriptional profile of S. erythraea. The expression of genes coding for key enzymes of carbon (and energy) and nitrogen central metabolism was dramatically altered in turn affecting the flux of metabolites through erythromycin feeder pathways. In particular, the valine catabolic pathway that supplies propionyl-CoA for biosynthesis of the erythromycin precursor 6-deoxyerythronolide B was strongly up-regulated in the S444F mutants, while the expression of the biosynthetic gene cluster of erythromycin (ery) was not significantly affected. In contrast, the ery cluster was down-regulated (<2-fold) in the Q426R mutants. These strains also exhibited an impressive stimulation of the nitrogen regulon, which may contribute to lower erythromycin yields as erythromycin production was strongly inhibited by ammonium.

Conclusion

Rifampicin selection is a simple and reliable tool to investigate novel links between primary and secondary metabolism and morphological differentiation in S. erythraea and to improve erythromycin production. At the same time genome-wide analysis of expression profiles using DNA microarrays allowed information to be gained about the mechanisms underlying the stimulatory/inhibitory effects of the rif mutations on erythromycin production.
Increased body mass and depressive symptomatology are associated with hypercholesterolemia, among elderly individuals; results from the MEDIS study
Authors: Tyrovolas Stefanos , Lionis Christos , Zeimbekis Akis , Bountziouka Vassiliki , Micheli Mary , Katsarou Alexia , Papairakleous Natassa , Metallinos George , Makri Kornilia , Polychronopoulos Evangelos , Panagiotakos Demosthenes B
Published: March 2009

Background

Hypercholesterolemia is one of the most important factors causing cardiovascular disease (CVD). The aim of the present work was to evaluate the relationships between socio-demographic, clinical, lifestyle and depression status and the presence of hypercholesterolemia, among elderly individuals without known CVD.

Methods

During 2005–2007, 1190 elderly (aged 65 to 100 years) men and women (from Cyprus, Mitilini, Samothraki, Cephalonia, Crete, Lemnos, Corfu and Zakynthos) were enrolled. Socio-demographic, clinical and lifestyle factors were assessed through standard procedures. Symptoms of depression were evaluated using the short-form of the Geriatric Depression Scale (GDS, range 0–15). Dietary habits were assessed through a semi-quantitative food frequency questionnaire. Hypercholesterolemia was defined as total serum cholesterol > 200 mg/dL or use of lipids lowering medication.

Results

44.6% of males and 61.9% of females had hypercholesterolemia (p < 0.001). Only, 63% of hypercholesterolemic participants were under special diet or pharmaceutical treatment. Hypercholisterolemic individuals had higher prevalence of obesity (43% vs. 25%), hypertension (76% vs. 57%) and diabetes (25% vs. 17%) compared with normal participants (p < 0.001). Furthermore, hypercholisterolemic participants showed higher depression levels (p = 0.002). After adjusting for various confounders, GDS score and BMI correlated with 13% (95%CI 0.98–1.30) and 14% (95%CI 0.99–1.31) higher likelihood of having hypercholesterolemia.

Conclusion

A considerable proportion of our elderly sample had hypercholesterolemia, while 1/3 of them were untreated. Furthermore, presence of hypercholesterolemia was correlated with depressive symptomatology and increased BMI.
Arachidonic acid increases matrix metalloproteinase 9 secretion and expression in human monocytic MonoMac 6 cells
Authors: Solakivi Tiina , Kunnas Tarja , Kärkkäinen Satu , Jaakkola Olli , Nikkari Seppo T
Published: March 2009

Background

Dietary fatty acids may modulate inflammation in macrophages of the atherosclerotic plaque, affecting its stability. The n-6 polyunsaturated fatty acid (PUFA) arachidonic acid (AA) generally promotes inflammation, while the PUFAs of the n-3 series eicosapentaenoic acid (EPA), docosapentaenoic acid (DPA) and docosahexaenoic acid (DHA) are considered anti-inflammatory. We determined how these PUFAs influence MMP-9 expression and secretion by the human monocytic cell line (MonoMac 6) at baseline and after 24-hour exposure. MMP-9 protein was measured by zymography and relative levels of MMP-9 mRNA were determined using quantitative real time PCR.

Results

Supplementation with AA (but not the n-3 fatty acids) increased, in a dose-dependent manner, expression of MMP-9 protein. This stimulation was regulated at the mRNA level. MMP-9 secretion started after 1 h of incubation and could not be prevented by simultaneous presence of n-3 series fatty acids. Finally, the secretion could be attenuated by LY 294002, a specific phosphatidylinositol-3-kinase (PI3K) inhibitor and by SH-5, a selective Akt inhibitor, suggesting that activation of PI3K by AA leads to augmented and sustained MMP-9 production.

Conclusion

This study shows that of the PUFA studied, AA alone influences the expression of MMP-9, which might have implications in MMP-9 induced plaque rupture.
HIV/AIDS in Vancouver, British Columbia: a growing epidemic
Authors: McInnes Colin W , Druyts Eric , Harvard Stephanie S , Gilbert Mark , Tyndall Mark W , Lima Viviane D , Wood Evan , Montaner Julio SG , Hogg Robert S
Published: March 2009

The prevalence of HIV in Vancouver, British Columbia was subject to two distinct periods of rapid increase. The first occurred in the 1980s due to high incidence among men who have sex with men (MSM), and the second occurred in the 1990s due to high incidence among injection drug users (IDU). The purpose of this study was to estimate and model the trends in HIV prevalence in Vancouver from 1980 to 2006. HIV prevalence data were entered into the UNAIDS/WHO Estimation and Projection Package (EPP) where prevalence trends were estimated by fitting an epidemiological model to the data. Epidemic curves were fit for IDU, MSM, street-based female sex trade workers (FSW), and the general population. Using EPP, these curves were then aggregated to produce a model of Vancouver's overall HIV prevalence. Of the 505 000 people over the age of 15 that reside in Vancouver, 6108 (ranging from 4979 to 7237) were living with HIV in the year 2006, giving an overall prevalence of 1.21 percent (ranging from 0.99 to 1.43 percent). The subgroups of IDU and MSM account for the greatest proportion of HIV infections. Our model estimates that the prevalence of HIV in Vancouver is greater than one percent, roughly 6 times higher than Canada's national prevalence. These results suggest that HIV infection is having a relatively large impact in Vancouver and that evidence-based prevention and harm reduction strategies should be expanded.
Defining behavioral and molecular differences between summer and migratory monarch butterflies
Authors: Zhu Haisun , Gegear Robert J , Casselman Amy , Kanginakudru Sriramana , Reppert Steven M
Published: March 2009

Background

In the fall, Eastern North American monarch butterflies (Danaus plexippus) undergo a magnificent long-range migration. In contrast to spring and summer butterflies, fall migrants are juvenile hormone deficient, which leads to reproductive arrest and increased longevity. Migrants also use a time-compensated sun compass to help them navigate in the south/southwesterly direction en route for Mexico. Central issues in this area are defining the relationship between juvenile hormone status and oriented flight, critical features that differentiate summer monarchs from fall migrants, and identifying molecular correlates of behavioral state.

Results

Here we show that increasing juvenile hormone activity to induce summer-like reproductive development in fall migrants does not alter directional flight behavior or its time-compensated orientation, as monitored in a flight simulator. Reproductive summer butterflies, in contrast, uniformly fail to exhibit directional, oriented flight. To define molecular correlates of behavioral state, we used microarray analysis of 9417 unique cDNA sequences. Gene expression profiles reveal a suite of 40 genes whose differential expression in brain correlates with oriented flight behavior in individual migrants, independent of juvenile hormone activity, thereby molecularly separating fall migrants from summer butterflies. Intriguing genes that are differentially regulated include the clock gene vrille and the locomotion-relevant tyramine beta hydroxylase gene. In addition, several differentially regulated genes (37.5% of total) are not annotated. We also identified 23 juvenile hormone-dependent genes in brain, which separate reproductive from non-reproductive monarchs; genes involved in longevity, fatty acid metabolism, and innate immunity are upregulated in non-reproductive (juvenile-hormone deficient) migrants.

Conclusion

The results link key behavioral traits with gene expression profiles in brain that differentiate migratory from summer butterflies and thus show that seasonal changes in genomic function help define the migratory state.
WSES SM (World Society of Emergency Surgery Summer Meeting) highlights: emergency surgery around the world (Brazil, Finland, USA)
Authors: Poggetti Renato , Leppanemi Ari , Ferrada Paula , Puyana Juan Carlos , Peitzman Andrew B , Ansaloni Luca , Catena Fausto , Pinna Antonio D , Moore Ernest E
Published: March 2009

Emergency surgery is performed in every hospital with a A and E unit all around the world. However it is organized in different ways with different results.

Aim of this paper is to present history, current scope, current training program and new politics for training national program of 3 countries of different continents.

Brazil, Finland and US emergency surgery models are presented discussing all criticisms showed during the WSES Summer Meeting 2008.
Overexpression of transketolase-like gene 1 is associated with cell proliferation in uterine cervix cancer
Authors: Chen Hui , Yue Jian-Xin , Yang Shou-Hua , Ding Hui , Zhao Rong-Wei , Zhang Song
Published: March 2009

Background

Tumor cells need large energy and nucleic acids to proliferate and grow. For most of their energy needs, cancer cells depend more on glycolysis. For most of their nucleic acids needs, cancer cells depend more on the nonoxidative pathway of the pentose phosphate pathway. Transketolase(TKT) is a crucial enzyme in the nonoxidative pathway of the PPP.

Methods

The real-time quantity PCR was used to determine the expression of transketolase gene family in uterine cervix cancer. Transketolase activity of cell was determined by using enzyme-linked method. Cell proliferation was detected by using MTT.

Results

The TKTL1 mRNA was specifically over-expressed in uterine cervix cancer cells(HeLa cell line) compare with normal human endocervical epithelial cells(End1/E6E7 cell line)(P < 0.05), whereas the expression of TKT and transketolase-like gene 2(TKTL2) have no significant differences between the two cell lines(P > 0.05). Moreover, we found that total transketolase activity was significantly reduced, and cell proliferation was remarkably inhibited after anti-TKTL1 siRNA treatment in HeLa cells. The total transketolase activity and cell proliferation have no significant differences after anti-TKTL1 siRNA treatment in End1/E6E7 cells.

Conclusion

These results indicate that TKTL1 plays an important role in total transketolase activity and cells proliferation in uterine cervix cancer.
Distribution and correlates of plantar hyperkeratotic lesions in older people
Authors: Spink Martin J , Menz Hylton B , Lord Stephen R
Published: March 2009

Background

Plantar hyperkeratotic lesions are common in older people and are associated with pain, mobility impairment and functional limitations. However, little has been documented in relation to the frequency or distribution of these lesions. The aim of this study was to document the occurrence of plantar hyperkeratotic lesions and the patterns in which they occur in a random sample of older people.

Methods

A medical history questionnaire was administered to a random sample of 301 people living independently in the community (117 men, 184 women) aged between 70 and 95 years (mean 77.2, SD 4.9), who also underwent a clinical assessment of foot problems, including the documentation of plantar lesion locations, toe deformities and the presence and severity of hallux valgus.

Results

Of the 301 participants, 180 (60%) had at least one plantar hyperkeratotic lesion. Those with plantar lesions were more likely to be female (χ2= 18.75,p< 0.01; OR = 2.86), have moderate to severe hallux valgus (χ2= 6.15,p< 0.02; OR = 2.95), a larger dorsiflexion range of motion at the ankle (39.4 ± 9.3vs36.3 ± 8.4°;t= 2.68,df= 286,p< 0.01), and spent more time on their feet at home (5.1 ± 1.0vs4.8 ± 1.3 hours,t= ‐2.46,df= 299,p= 0.01). No associations were found between the presence of plantar lesions and body mass index, obesity, foot posture, dominant foot or forefoot pain. A total of 53 different lesions patterns were observed, with the most common lesion pattern being “roll‐off” hyperkeratosis on the medial aspect of the 1stmetatarsophalangeal joint (MPJ), accounting for 12% of all lesion patterns. “Roll‐off” lesions under the 1stMPJ and interphalangeal joint were significantly associated with moderate to severe hallux valgus (p< 0.05), whereas lesions under the central MPJs were significantly associated with deformity of the corresponding lesser toe (p< 0.05). Factor analysis indicated that 62% of lesion patterns could be grouped under three broad categories, relating to medial, central and lateral locations.

Conclusion

Plantar hyperkeratotic lesions affect 60% of older people and are associated with female gender, hallux valgus, toe deformity, increased ankle flexibility and time spent on feet, but are not associated with obesity, limb dominance, forefoot pain or foot posture. Although there are a wide range of lesion distribution patterns, most can be classified into medial, central or lateral groups. Further research is required to determine whether these patterns are related to the dynamic function of the foot or other factors such as foot pathology or morphology.
Candida albicansinduces cyclo-oxygenase 2 expression and prostaglandin E2 production in synovial fibroblasts through an extracellular-regulated kinase 1/2 dependent pathway
Authors: Lee Herng-Sheng , Lee Chung-Shinn , Yang Chi-Jung , Su Sui-Long , Salter Donald M
Published: March 2009

Introduction

Synovial cells are potential sources of inflammatory mediators in bacterial-induced arthritis but their involvement in the inflammatory response to Candida albicans-induced septic arthritis is largely unknown.

Methods

Primary cultures of rat synovial fibroblasts were infected with C. albicans (ATCC90028). Immunocytochemistry, western blotting, and RT-PCR were performed to assess cyclo-oxygenase 2 induction. Phosphorylation of extracellular-regulated kinase (ERK1/2) following infection in the absence or presence of U0126 was assessed by western blotting whilst prostaglandin E2 production was measured by ELISA. Nuclear factor κB (NFκB) translocation was evaluated by an electrophoretic mobility shift assay.

Results

Infection of synovial fibroblasts with C. albicans resulted in cyclo-oxygenase 2 expression and prostaglandin E2 production. Cyclo-oxygenase 2 expression and prostaglandin E2 production was dependent upon extracellular-regulated kinase 1/2 phosphorylation, associated with activation of NFκB and significantly elevated in the presence of laminarin, an inhibitor of dectin-1 activity. Synovial fibroblasts adjacent to C. albicans hyphae aggregates appeared to be the major contributors to the increased levels of cyclo-oxygenase 2 and phosphorylated extracellular-regulated kinase 1/2.

Conclusions

C. albicans infection of synovial fibroblasts in vitro results in upregulation of cyclo-oxygenase 2 and prostaglandin E2 by mechanisms that may involve activation of extracellular-regulated kinase 1/2 and are associated with NFκB activation.
Mortality and tardive dyskinesia: long-term study using the US National Death Index
Authors: Dean Charles E. , Thuras Paul D.
Published: March 2009

Background

Whether the development of tardive dyskinesia leads to an increase in mortality is still unclear.

Aims

To explore the relationship between tardive dyskinesia and mortality over a 10-year period, using the National Death Index.

Method

Death certificates were obtained from the National Death Index on 1621 people repeatedly assessed for tardive dyskinesia by trained raters. Variables with the potential for influencing survival time were also investigated.

Results

Tardive dyskinesia was significantly associated with an increase in mortality (P<0.001), but this association became non-significant when drug course and age were entered in the regression analysis. Those who had taken only conventional antipsychotics were twice as likely to die compared with those taking atypical agents (P<0.02). For those aged 53–65 years, conventional agents were associated with a sevenfold increase in mortality.

Conclusions

Older individuals with tardive dyskinesia treated with conventional antipsychotics appear to have a shortened survival time.
Molecular differentiation of schizoaffective disorder from schizophrenia usingBDNFhaplotypes
Authors: Lencz Todd , Lipsky Robert H. , DeRosse Pamela , Burdick Katherine E. , Kane John M. , Malhotra Anil K.
Published: March 2009

Background

Allelic variation in the gene encoding brain-derived neurotrophic factor (BDNF) has been associated with affective disorders, but generally not schizophrenia. Brain-derived neurotrophic factor variants may help clarify the status of schizoaffective disorder.

Aims

To test the hypothesis thatBDNFhaplotypes are associated with psychiatric illness marked by a prominent affective component.

Method

Frequencies of a 5-markerBDNFhaplotype were examined in 600 White participants across four diagnostic categories and healthy controls.

Results

Individuals with schizoaffective disorder and other affective disorders were significantly more likely to carry two copies of the most commonBDNFhaplotype (containing the valine allele of the Val66Met polymorphism) compared with healthy volunteers. Moreover, when compared with people with schizophrenia, individuals with schizoaffective disorder were significantly more likely to carry two copies of the common haplotype.

Conclusions

To our knowledge, this is the first candidate gene study to demonstrate association with schizoaffective disorder but not schizophrenia. Variation in theBDNFgene may be associated with the clinical phenotype of affective dysregulation across several DSM–IV diagnostic categories.
Anandamide elevation in cerebrospinal fluid in initial prodromal states of psychosis
Authors: Koethe Dagmar , Giuffrida Andrea , Schreiber Daniela , Hellmich Martin , Schultze-Lutter Frauke , Ruhrmann Stefan , Klosterkötter Joachim , Piomelli Daniele , Leweke F. Markus
Published: March 2009

Anandamide is a bioactive lipid binding to cannabinoid receptors. A homeostatic role for anandamide has been suggested in schizophrenia. We investigated its role in initial prodromal states of psychosis. We measured the levels of anandamide and its structural analog oleoylethanolamide in cerebrospinal fluid and serum of patients in the initial prodromal state (n=27) alongside healthy volunteers (n=81) using high-performance liquid chromatograph/mass spectrometry. Cerebrospinal anandamide levels in patients were significantly elevated. Patients with lower levels showed a higher risk for transiting to psychosis earlier. This anandamidergic up-regulation in the initial prodromal course may suggest a protective role of the endocannabinoid system in early schizophrenia.
Psychiatric out-patient clinics for older adults: highly regarded by users and carers, but irreplaceable?
Authors: Negi Rashi , Seymour Jeremy , Flemons Christopher , Impey Matthew , Thomas Nicola , Witrylak Rachael
Published: March 2009

Aims and Method

The aim of this study was to explore older users' and carers' views of attending out-patient clinics for older adults. A questionnaire was designed to be distributed to all patients attending out-patient clinics for a period of 1 month in January 2007.

Results

The response rate for returning the completed questionnaire was 71%, and 95% of these respondents were satisfied with their overall experience of attending out-patient clinics. Although satisfaction levels were high with every aspect of out-patient clinics, 49% preferred the hypothetical option of being seen at home.

Clinical Implications

The role of psychiatric out-patient departments for older adults merits further research, comparing cost and user/carer acceptability with home or general practitioner surgery-based treatment.
The Communication Group: bringing group psychotherapy back to acute in-patient psychiatry
Authors: Grandison Alistair L. , Pharwaha Bhupinderjit Kaur , Jefford Adam , Dratcu Luiz
Published: March 2009

People who are admitted to acute psychiatric wards need psychological as well as pharmacological treatments, but psychological care is not always available in the acute setting. Group psychotherapy can prove a practical and cost-effective answer to this unmet need in service provision. We describe a psychotherapeutic group that our team has implemented on our busy, inner-city, male-only acute ward, which has been running successfully for over 2 years and has since become an integral part of the acute care we provide to our in-patients. Group therapy can enhance individuals' adherence to treatment plans, reduce reliance on pharmacological approaches, pre-empt untoward serious incidents and potentially reduce patients' duration of stay. In addition to addressing the psychological needs of acutely unwell people, group therapy is beneficial to the clinical team by promoting a better work and therapeutic environment on the ward.
Will the CASC stand the test? A review and critical evaluation of the new MRCPsych clinical examination
Authors: Thompson Catherine M.
Published: March 2009

The aim of this paper is to review and critically evaluate the Clinical Assessment of Skills and Competencies (CASC) examination, introduced in June 2008. the history of clinical membership examinations and rationale for the new examination are considered. the development and implementation of the examination is described by means of a four-step model of assessment. Finally, the paper critically evaluates the assessment with reference to validity, reliability, practicability and effect on learner.
Multicenter Validation of a 1,550-Gene Expression Profile for Identification of Tumor Tissue of Origin
Authors: Monzon Federico A. , Lyons-Weiler Maureen , Buturovic Ljubomir J. , Rigl C. Ted , Henner W. David , Sciulli Christin , Dumur Catherine I. , Medeiros Fabiola , Anderson Glenda G.
Published: March 2009

Purpose

Malignancies found in unexpected locations or with poorly differentiated morphologies can pose a significant challenge for tissue of origin determination. Current histologic and imaging techniques fail to yield definitive identification of the tissue of origin in a significant number of cases. The aim of this study was to validate a predefined 1,550-gene expression profile for this purpose.

Methods

Four institutions processed 547 frozen specimens representing 15 tissues of origin using oligonucleotide microarrays. Half of the specimens were metastatic tumors, with the remainder being poorly differentiated and undifferentiated primary cancers chosen to resemble those that present as a clinical challenge.

Results

In this blinded multicenter validation study the 1,550-gene expression profile was highly informative in tissue determination. The study found overall sensitivity (positive percent agreement with reference diagnosis) of 87.8% (95% CI, 84.7% to 90.4%) and overall specificity (negative percent agreement with reference diagnosis) of 99.4% (95% CI, 98.3% to 99.9%). Performance within the subgroup of metastatic tumors (n = 258) was found to be slightly lower than that of the poorly differentiated and undifferentiated primary tumor subgroup, 84.5% and 90.7%, respectively (P = .04). Differences between individual laboratories were not statistically significant.

Conclusion

This study represents the first adequately sized, multicenter validation of a gene-expression profile for tissue of origin determination restricted to poorly differentiated and undifferentiated primary cancers and metastatic tumors. These results indicate that this profile should be a valuable addition or alternative to currently available diagnostic methods for the evaluation of uncertain primary cancers.
Autologous Stem-Cell Transplantation in Patients With HIV-Related Lymphoma
Authors: Balsalobre Pascual , Díez-Martín José L. , Re Alessandro , Michieli Mariagrazia , Ribera José M. , Canals Carmen , Rosselet Anne , Conde Eulogio , Varela Rosario , Cwynarski Kate , Gabriel Ian , Genet Philippe , Guillerm Gaelle , Allione Bernardino , Ferrant Augustin , Biron Pierre , Espigado Ildefonso , Serrano David , Sureda Anna
Published: March 2009

Purpose

Peripheral-blood autologous stem-cell transplantation (ASCT) in patients with HIV-related lymphoma (HIV-Ly) has been reported as a safe and useful procedure. Herein we report the European Group for Blood and Marrow Transplantation experience on patients with HIV-Ly undergoing ASCT.

Patients and Methods

This was a retrospective, multicentric, registry-based analysis.

Results

Since 1999, 68 patients from 20 institutions (median age, 41 years; range, 29 to 62 years) were included, diagnosed with non-Hodgkin's lymphoma (NHL; n = 50) or Hodgkin's lymphoma (n = 18). At the time of ASCT, 16 patients were in first complete remission (CR1); 44 patients were in CR more than 1, partial remission, or chemotherapy-sensitive relapse (chemo-S); and eight patients had chemotherapy-resistant disease. The median number of CD34+ cells infused was 4.5 × 106/kg (range, 1.6 to 21.2 × 106/kg). Median time to neutrophil and platelet engraftment were 11 days (range, 8 to 36 days) and 14 days (range, 6 to 455 days), respectively, with a cumulative incidence (CI) at 1 year of 95.6% and 87%, respectively. CI of nonrelapse mortality (NRM) was 7.5% at 12 months after ASCT, mainly because of bacterial infections. CI of relapse was 30.4% at 24 months, statistically related with not being in CR at ASCT (relative risk [RR] = 3.6), NHL histology other than diffuse large B-cell lymphoma (RR = 3.4), and use of more than two previous treatment lines (RR = 3). At a median follow-up of 32 months (range, 2 to 81 months), progression-free survival (PFS) was 56%. Patients not in CR or with refractory disease at ASCT had poorer PFS (RR = 2.4 and 4.8, respectively).

Conclusion

Similarly to HIV-negative patients with lymphoma, ASCT is a useful treatment for patients with HIV-Ly and is associated with low NRM, mainly when performed in early stages and chemo-S disease.
Vandetanib Versus Gefitinib in Patients With Advanced Non–Small-Cell Lung Cancer: Results From a Two-Part, Double-Blind, Randomized Phase II Study
Authors: Natale Ronald B. , Bodkin David , Govindan Ramaswamy , Sleckman Bethany G. , Rizvi Naiyer A. , Capó Adolfo , Germonpré Paul , Eberhardt Wilfried E.E. , Stockman Paul K. , Kennedy Sarah J. , Ranson Malcolm
Published: March 2009

Purpose

Vandetanib is a once-daily oral inhibitor of vascular endothelial growth factor receptor (VEGFR) and epidermal growth factor receptor (EGFR) signaling. In this two-part phase II study, the efficacy and safety of vandetanib was compared with that of gefitinib, an inhibitor of EGFR signaling.

Patients and Methods

Patients (N = 168) with locally advanced or metastatic (stage IIIB/IV) non–small-cell lung cancer (NSCLC), after failure of first-line with or without second-line platinum-based chemotherapy, received once-daily vandetanib 300 mg (n = 83) or gefitinib 250 mg (n = 85) until disease progression or evidence of toxicity (part A). After a 4-week washout period, eligible patients had the option to switch to the alternative treatment (part B). Progression-free survival (PFS) was the primary efficacy assessment in part A, which was designed to have a higher than 75% power to detect a 33% prolongation of PFS at a one-sided significance level of .2.

Results

In part A, vandetanib prolonged PFS compared with gefitinib (hazard ratio = 0.69; 95% CI, 0.50 to 0.96; one-sided P = .013). Patients receiving vandetanib experienced adverse events that were manageable and generally consistent with inhibition of EGFR and VEGFR signaling, including diarrhea, rash, and hypertension. There were no unexpected safety findings with gefitinib. Overall survival, a secondary assessment, was not significantly different between patients initially randomly assigned to either vandetanib or gefitinib.

Conclusion

The primary efficacy objective was achieved, with vandetanib demonstrating a significant prolongation of PFS versus gefitinib. Vandetanib 300 mg/d is currently being evaluated as a monotherapy in two randomized phase III studies in advanced NSCLC.
Long-Term Outcome of Cirrhotic Patients With Early Hepatocellular Carcinoma Treated With Ultrasound-Guided Percutaneous Laser Ablation: A Retrospective Analysis
Authors: Pacella Claudio Maurizio , Francica Giampiero , Di Lascio Francesca Marta Lilja , Arienti Vincenzo , Antico Ettore , Caspani Bruno , Magnolfi Fabrizio , Megna Angelo Salomone , Pretolani Stefano , Regine Renato , Sponza Massimo , Stasi Roberto
Published: March 2009

Purpose

Percutaneous laser ablation (PLA) has been proposed as an active treatment in patients with hepatocellular carcinoma (HCC). However, large multicenter studies using this technique have not been reported.

Patients and Methods

We retrospectively analyzed treatment and survival parameters of 432 cirrhotic patients with nonsurgical early HCC (single nodule ≤ 4 cm or three nodules ≤ 3 cm each) who had received PLA in nine Italian centers.

Results

Single tumors were seen in 344 (80%) of 432 patients, and two to three nodules were seen in 88 patients (20%), for a total of 548 tumors. An initial complete response after PLA was observed in 338 patients (78%). Median overall survival time was 47 months (95% CI, 41 to 53 months). The 3- and 5-year cumulative survival rates were 61% and 34%, respectively. In multivariate analysis, independent predictors of survival were serum albumin levels more than 3.5 g/dL (P = .002; risk ratio [RR] = 0.580; 95% CI, 0.409 to 0.821), the achievement of a complete tumor ablation (P = .001; RR = 0.517; 95% CI, 0.346 to 0.771), and age less than 73 years (P < .001; RR = 0.466; 95% CI, 0.320 to 0.681). Child-Turcotte-Pugh class A patients had a 5-year cumulative survival rate of 41%; this figure increased up to 60% with a median survival time of 63 months (95% CI, 48 to 78 months) in patients with tumors ≤ 2.0 cm.

Conclusion

This analysis confirms that a complete tumor ablation results in improved survival in patients with nonsurgical HCC. Ideal candidates for PLA are younger patients with normal serum albumin levels and tumor size ≤ 2 cm.
Pharmacogenetic Analyses of a Phase III Trial in Metastatic Gastroesophageal Adenocarcinoma With Fluorouracil and Leucovorin Plus Either Oxaliplatin or Cisplatin: A Study of the Arbeitsgemeinschaft Internistische Onkologie
Authors: Goekkurt Eray , Al-Batran Salah-Eddin , Hartmann Jörg T. , Mogck Ulrike , Schuch Gunter , Kramer Michael , Jaeger Elke , Bokemeyer Carsten , Ehninger Gerhard , Stoehlmacher Jan
Published: March 2009

Purpose

To evaluate the association of germ-line polymorphisms of genes that may impact treatment outcome of platinum and fluorouracil combination chemotherapy in advanced gastric cancer (AGC).

Patients and Methods

Blood samples of 156 patients enrolled onto a phase III study comparing fluorouracil, leucovorin, and oxaliplatin with fluorouracil, leucovorin, and cisplatin were collected. Polymorphisms within genes of TS, MTHFR, MTR, OPRT, XPD, ERCC1, XRCC1, XPA, GSTP1, GSTT1, and GSTM1 were genotyped using polymerase chain reaction–based techniques.

Results

Median overall survival (OS) was 11.8 months (95% CI, 9.75 to 13.79 months) and median progression-free survival (PFS) was 5.8 months (95% CI, 4.99 to 6.61 months). The TS-3R/+6 haplotype (P = .004), the GSTT1 deletion polymorphism (P = .015), and genotypes of OPRT-Gly213Ala (P = .003) and XRCC1-Arg399Gln (P = .023) could be identified as independent predictors of OS. For PFS analyses, the TS-3R/+6 haplotye (P = .003) and MTR-A2756G (P = .01) were identified as independent positive predictors. The association between the GSTT1 deletion polymorphism and PFS showed only borderline significance (P = .053). Treatment related hematotoxicity in terms of grade 3/4 leukopenia was lowest among TS-3R/+6 haplotype carriers (P = .037). Grade 3/4 neutropenia was directly associated with the MTR-2756G/G genotype (P = .011), GSTP1-105Ile/Ile genotype (P = .02), and with the ERCC1-118T/8092C-haplotype (P = .042). In addition, significant associations between GSTP1-105Ile/Ile genotype and neurotoxicity and between the XPD-Asn312/751Gln haplotype and nephrotoxicity could be identified (P = .028 and P = .005, respectively).

Conclusion

These findings underline the hypothesis that germ-line polymorphisms may play an important role in individualizing chemotherapy in AGC and deserve further prospective evaluation in AGC patients.
Phase III Trial Evaluating the Addition of Paclitaxel to Doxorubicin Followed by Cyclophosphamide, Methotrexate, and Fluorouracil, As Adjuvant or Primary Systemic Therapy: European Cooperative Trial in Operable Breast Cancer
Authors: Gianni Luca , Baselga José , Eiermann Wolfgang , Porta Vincente Guillem , Semiglazov Vladimir , Lluch Aňa , Zambetti Milvia , Sabadell Dolores , Raab Günther , Cussac Antonio Llombart , Bozhok Alla , Martinez-Agulló Angel , Greco Marco , Byakhov Mikhail , Lopez Juan Josè Lopez , Mansutti Mauro , Valagussa Pinuccia , Bonadonna Gianni
Published: March 2009

Purpose

To evaluate the addition of paclitaxel to an anthracycline-based adjuvant regimen and to compare this combination with the same regimen given as primary systemic (neoadjuvant) therapy.

Patients and Methods

A total of 1,355 women with operable breast cancer were randomly assigned to one of three treatments: surgery followed by adjuvant doxorubicin (75 mg/m2) followed by cyclophosphamide, methotrexate, and fluorouracil (CMF; arm A); surgery followed by adjuvant paclitaxel (200 mg/m2) plus doxorubicin (60 mg/m2), followed by CMF (arm B); or paclitaxel (200 mg/m2) plus doxorubicin (60 mg/m2) followed by CMF followed by surgery (arm C). The two coprimary objectives were to assess the effects on relapse-free survival (RFS) of the addition of paclitaxel to postoperative chemotherapy (arm B v arm A) and primary chemotherapy versus adjuvant chemotherapy (arm B v arm C).

Results

Doxorubicin plus paclitaxel followed by CMF was well-tolerated as adjuvant or as primary chemotherapy. The addition of paclitaxel to adjuvant doxorubicin followed by CMF significantly improved RFS compared with adjuvant doxorubicin alone followed by CMF (hazard ratio [HR], 0.73; P = .03). Distant RFS was similarly improved (HR, 0.70; P = .027). There was no significant difference in RFS when the paclitaxel/doxorubicin/CMF chemotherapy was given before surgery compared with the same regimen given after surgery (HR, 1.21; P = .18). However, the rate of breast-conserving surgery was significantly higher with preoperative chemotherapy (63% v 34%; P < .001).

Conclusion

Incorporating paclitaxel into anthracycline-based adjuvant therapy resulted in a significant improvement in RFS and distant RFS. When given as primary systemic therapy, the paclitaxel-containing regimen allowed breast-sparing surgery in a significant percentage of patients.
Prospective Validation of a Prognostic Score to Improve Patient Selection for Oncology Phase I Trials
Authors: Arkenau Hendrik-Tobias , Barriuso Jorge , Olmos David , Ang Joo Ern , de Bono Johann , Judson Ian , Kaye Stan
Published: March 2009

Purpose

With the aim of improving patient selection for phase I trials, we previously performed a retrospective analysis of 212 phase I oncology patients where we were able to develop a prognostic score predicting overall survival (OS). This prospective study was performed to test the validity of the prognostic score.

Patients and Methods

On the basis of our retrospective multivariate analysis, three factors were associated with poor survival (albumin < 35 g/L, lactate dehydrogenase [LDH] > upper limit of normal [ULN], and > two sites of metastases). We integrated these into a prognostic score ranging from 0 to 3 and analyzed this score in a prospectively selected cohort of 78 patients enrolled onto phase I trials.

Results

All patients had progressive disease before study entry. The median age was 56 years (range, 18 to 79 years). After a median follow-up time of 27.3 weeks, patients with a prognostic score of 0 to 1 (n = 43) had superior OS (33.0 weeks; 95% CI, 24 to 42 weeks) compared with patients with a score of 2 to 3 (n = 35; 15.7 weeks; 95% CI, 11 to 21 weeks). Our multivariate analysis confirmed that our prognostic score was an independent marker for OS, with a hazard ratio of 1.4 (95% CI, 1.02 to 1.9; P = .036).

Conclusion

This is the first prospective analysis confirming that a prognostic score based on objective markers, including albumin less than 35 g/L, LDH more than ULN, and more than two sites of metastasis, is a helpful tool in the process of patient selection for phase I trial entry.
Edema Control by Cediranib, a Vascular Endothelial Growth Factor Receptor–Targeted Kinase Inhibitor, Prolongs Survival Despite Persistent Brain Tumor Growth in Mice
Authors: Kamoun Walid S. , Ley Carsten D. , Farrar Christian T. , Duyverman Annique M. , Lahdenranta Johanna , Lacorre Delphine A. , Batchelor Tracy T. , di Tomaso Emmanuelle , Duda Dan G. , Munn Lance L. , Fukumura Dai , Sorensen A. Gregory , Jain Rakesh K.
Published: March 2009

Purpose

Recent clinical trials of antivascular endothelial growth factor (VEGF) agents for glioblastoma showed promising progression-free and overall survival rates. However, available clinical imaging does not separate antitumor effects from antipermeability effects of these agents. Thus although anti-VEGF agents may decrease tumor contrast-enhancement, vascularity, and edema, the mechanisms leading to improved survival in patients remain incompletely understood. Our goal was to determine whether alleviation of edema by anti-VEGF agents alone could increase survival in mice.

Methods

We treated mice bearing three different orthotopic models of glioblastoma with a VEGF-targeted kinase inhibitor, cediranib. Using intravital microscopy, molecular techniques, and magnetic resonance imaging (MRI), we measured survival, tumor growth, edema, vascular morphology and function, cancer cell apoptosis and proliferation, and circulating angiogenic biomarkers.

Results

We show by intravital microscopy that cediranib significantly decreased tumor vessel permeability and diameter. Moreover, cediranib treatment induced normalization of perivascular cell coverage and thinning of the basement membrane, as mirrored by an increase in plasma collagen IV. These rapid changes in tumor vascular morphology and function led to edema alleviation—as measured by MRI and by dry/wet weight measurement of water content—but did not affect tumor growth. By immunohistochemistry, we found a transient decrease in macrophage infiltration and significant but minor changes in tumor cell proliferation and apoptosis. Systemically, cediranib increased plasma VEGF and placenta growth factor levels, and the number of circulating CXCR4+CD45+ cells. However, by controlling edema, cediranib significantly increased survival of mice in the face of persistent tumor growth.

Conclusion

Anti-VEGF agents may be able to improve survival of patients with glioblastoma, even without inhibiting tumor growth.