bluuebunny/crossref_metadata_2025 huggingface dataset:
Identification of myxobacteria-derived HIV inhibitors by a high-throughput two-step infectivity assay
Authors: Martinez Javier P , Hinkelmann Bettina , Fleta-Soriano Eric , Steinmetz Heinrich , Jansen Rolf , Diez Juana , Frank Ronald , Sasse Florenz , Meyerhans Andreas
Published: September 2013

Background

Drug-resistance and therapy failure due to drug-drug interactions are the main challenges in current treatment against Human Immunodeficiency Virus (HIV) infection. As such, there is a continuous need for the development of new and more potent anti-HIV drugs. Here we established a high-throughput screen based on the highly permissive TZM-bl cell line to identify novel HIV inhibitors. The assay allows discriminating compounds acting on early and/or late steps of the HIV replication cycle.

Results

The platform was used to screen a unique library of secondary metabolites derived from myxobacteria. Several hits with good anti-HIV profiles were identified. Five of the initial hits were tested for their antiviral potency. Four myxobacterial compounds, sulfangolid C, soraphen F, epothilon D and spirangien B, showed EC50 values in the nM range with SI > 15. Interestingly, we found a high amount of overlapping hits compared with a previous screen for Hepatitis C Virus (HCV) using the same library.

Conclusion

The unique structures and mode-of-actions of these natural compounds make myxobacteria an attractive source of chemicals for the development of broad-spectrum antivirals. Further biological and structural studies of our initial hits might help recognize smaller drug-like derivatives that in turn could be synthesized and further optimized.
Oncostatin M stimulates cell migration and proliferation by down-regulating E-cadherin in HTR8/SVneo cell line through STAT3 activation
Authors: Ko Hyun Sun , Choi Sae Kyung , Kang Hee Kyung , Kim Ho Shik , Jeon Ji Hyun , Park In Yang , Shin Jong Chul
Published: September 2013

Background

During the first trimester of pregnancy, trophoblastic E-cadherin expression is down-regulated, thereby allowing extravillous trophoblasts (EVTs) to acquire the potential for migration and invasiveness. The aim of the present study was to investigate the role of OSM on the migration and proliferation of EVT cell line HTR8/SVneo with regard to its effects on the expression of E-cadherin and STAT3 activation.

Methods

We investigated the effects of OSM on RNA and protein expression of E-cadherin by real time RT-PCR analyses, western blotting, and indirect immunofluorescence staining in HTR8/SVneo cells, as well as the effects on cell migration and proliferation. The selective signal transducer and activator of transcription (STAT)3 inhibitor, stattic, and STAT3 siRNA were used to investigate STAT3 activation by OSM.

Results

OSM significantly reduced RNA and protein expression of E-cadherin. Indirect immunofluorescence staining of HTR8/SVneo cells also revealed the down-regulation of E-cadherin, compared with the controls. OSM-stimulated cell migration was attenuated by anti-gp130 antibodies. OSM-induced STAT3 phosphorylation, and the down-regulation of E-cadherin by OSM treatment was restored by stattic and STAT3 siRNA. In addition, OSM-stimulated migration and proliferation were significantly suppressed by STAT3 inhibition.

Conclusions

This study suggests that OSM stimulates the migration and proliferation of EVTs during the first trimester of pregnancy through the down-regulation of E-cadherin. In addition, this study suggests that the effects of OSM on migration and proliferation are related to STAT3 activation, which is important in trophoblast invasiveness.
The influence of passivation and photovoltaic properties of α-Si:H coverage on silicon nanowire array solar cells
Authors: Li KunTang , Wang XiuQin , Lu PengFei , Ding JianNing , Yuan NingYi
Published: September 2013

Silicon nanowire (SiNW) arrays for radial p-n junction solar cells offer potential advantages of light trapping effects and quick charge collection. Nevertheless, lower open circuit voltages (V
oc) lead to lower energy conversion efficiencies. In such cases, the performance of the solar cells depends critically on the quality of the SiNW interfaces. In this study, SiNW core-shell solar cells have been fabricated by growing crystalline silicon (c-Si) nanowires via the metal-assisted chemical etching method and by depositing hydrogenated amorphous silicon (α-Si:H) via the plasma-enhanced chemical vapor deposition (PECVD) method. The influence of deposition parameters on the coverage and, consequently, the passivation and photovoltaic properties of α-Si:H layers on SiNW solar cells have been analyzed.
Evaluation of the Housing First program in patients with severe mental disorders in France: study protocol for a randomized controlled trial
Authors: Tinland Aurelie , Fortanier Cecile , Girard Vincent , Laval Christian , Videau Benjamin , Rhenter Pauline , Greacen Tim , Falissard Bruno , Apostolidis Themis , Lançon Christophe , Boyer Laurent , Auquier Pascal
Published: September 2013

Background

Recent studies in North American contexts have suggested that the Housing First model is a promising strategy for providing effective services to homeless people with mental illness. In the context of the highly generous French national health and social care system, which is easily accessible and does not require out-of-pocket payment, the French Health Ministry insists on rigorous techniques, including randomized protocols, to evaluate the impact of Housing First approaches in France.

Method and design

A prospective randomized trial was designed to assess the impact of a Housing First intervention on health outcomes and costs over a period of 24 months on homeless people with severe mental illness, compared to Treatment-As-Usual. The study is being conducted in four cities in France: Lille, Marseille, Paris and Toulouse. The inclusion criteria are as follows: over 18 years of age, absolutely homeless or in precarious housing, and possessing a ‘high’ level of need: diagnosis of schizophrenia or bipolar disorder and moderate to severe disability according to the Multnomah Community Ability Scale (score ≤ 62) and at least one of the following three criteria: 1) having been hospitalized for mental illness two or more times in any one year during the preceding five years; 2) co-morbid alcohol or substance use; and 3) having been recently arrested or incarcerated. Participants will be randomized to receiving the Housing First intervention or Treatment-As-Usual. The Housing First intervention provides immediate access to independent housing and community care. The primary outcome criterion is the use of high-cost health services (that is,, number of hospital admissions and number of emergency department visits) during the 24-month follow-up period. Secondary outcome measures include health outcomes, social functioning, housing stability and contact with police services. An evaluation of the cost-effectiveness and cost-utility of Housing First will also be conducted. A total of 300 individuals per group will be included.

Discussion

This is the first study to examine the impact of a Housing First intervention compared to Treatment-As-Usual in France. It should provide key information to policymakers concerning the cost-effectiveness and health outcomes of the Housing First model in the French context.

Trial registration

The current clinical trial number is NCT01570712
Intermittent preventive treatment: efficacy and safety of sulfadoxine-pyrimethamine and sulfadoxine-pyrimethamine plus piperaquine regimens in schoolchildren of the Democratic Republic of Congo: a study protocol for a randomized controlled trial
Authors: Doua Joachim Yorokpa , Matangila Junior , Lutumba Pascal , Van geertruyden Jean-Pierre
Published: September 2013

Background

In malaria endemic areas, schoolchildren usually have asymptomatic malaria infections and consequently remain untreated. Therefore, intermittent preventive treatment with sulfadoxine-pyrimethamine in schoolchildren would be a plausible strategy in malaria stable transmission areas to prevent anaemia and malnutrition. However, in contrast to infancy and pregnancy, antimalaria intermittent preventive treatment in children has been barely investigated. As the implementation of intermittent preventive treatment may be challenged by sulfadoxine-pyrimethamine resistance, sulfadoxine-pyrimethamine combined with piperaquine may be a better alternative than sulfadoxine-pyrimethamine monotherapy. A clinical trial is being conducted to assess the efficacy and safety of intermittent preventive treatments versus controls in Democratic Republic of Congo (DRCongo) schoolchildren and their impact on sulfadoxine-pyrimethamine resistance.

Methods/Design

A phase IIIb, randomised, controlled trial will enroll asymptomatic schoolchildren. For interventions, sulfadoxine-pyrimethamine is compared to sulfadoxine-pyrimethamine plus piperaquine and to a control group. The two treatments are given four-monthly from baseline for a year as a single dose for sulfadoxine-pyrimethamine and two doses at 24-hour intervals for piperaquine. All participants receive praziquantel and albendazole as mass-treatment for helminthiasis at enrolment. The primary endpoint is haemoglobin concentration change at 12 months follow-up. Secondary endpoints are malaria parasite load and malaria prevalence, at baseline and at month 12. Malaria and helminthiasis incidence will be monitored throughout the study. Statistical analysis will use multilevel modelling due to repeated measurements and clustering effect of participants.

Discussion

The very few studies on intermittent preventive treatment in schoolchildren in malaria stable transmission areas have contradictory results. This randomised controlled trial is unique in comparing efficacy and safety of a prophylactic combination therapy to monotherapy or a control group after 12 months follow-up. Resistance markers for sulfadoxine-pyrimethamine (including break through parasitaemias) will also be recorded. Its uniqueness lies also in the fact that we use piperaquine, a long acting antimalarial, in combination with sulfadoxine-pyrimethamine. Artemisinin derivatives have been excluded as it is part of the treatment policies in virtually all malaria endemic countries. Our findings may, therefore, contribute to the public health of youngsters who fail to thrive and grow due to multiple morbidities.

Trial registration

NCT01722539; PACTR201211000449323
Chloramphenicol acetyltransferase as a selection marker for chlamydial transformation
Authors: Xu Shuang , Battaglia Lauren , Bao Xiaofeng , Fan Huizhou
Published: September 2013

Background

Chlamydia is a common bacterial pathogen responsible for many diseases. Methods for transforming this important organism using a β-lactamase as a selection marker have been developed very recently. However, the National Institutes of Health Guidelines for Research Involving Recombinant DNA Molecules do not permit transformation experiments with β-lactamase gene-containing vectors for certain human chlamydial pathogens. Therefore, a different selection marker is urgently needed for transformation of those chlamydiae.

Results

After transformation of plasmid-free Chlamydia trachomatis with pGFP:SW2, which carries a β-lactamase and a chloramphenicol acetyltransferase gene fused to a green fluorescence protein gene, transformants were obtained by selection with either ampicillin or chloramphenicol. Stable chloramphenicol-resistant, but ampicillin-sensitive, transformants were obtained using a pGFP:SW2 derivative without the β-lactamase. All transformants expressed green fluorescence protein and had glycogen synthesis activity restored.

Conclusions

Chloramphenicol resistance may be used as a selection marker for genetic experiments in Chlamydia. This eliminates the requirement for the use of β-lactamase, of which dissemination to some C. trachomatis serovars may jeopardize clinical treatment of chlamydial infections in pregnant women. Chloramphenicol acetyltransferase may also serve as a useful secondary selection marker for genetic analyses in β-lactamase-transformed chlamydial strains.
The effectiveness of salicylic acid plasters compared with ‘usual’ scalpel debridement of corns: a randomised controlled trial
Authors: Farndon Lisa J , Vernon Wesley , Walters Stephen J , Dixon Simon , Bradburn Mike , Concannon Michael , Potter Julia
Published: September 2013

Background

Corns are a common foot problem and surveys have indicated that between 14‐48% of people suffer from them. Many of these will seek podiatry treatment, however there is little evidence to indicate which current treatments provide long term resolution. This study compared ‘usual’ treatment (enucleation with a scalpel) with the application of 40% salicylic acid plasters to corns to investigate which is the most effective in terms of clinical, economic and patient‐centred outcomes.

Methods

A parallel‐group randomised controlled trial was carried out in two centres where adults who presented with one or more corns and who met the inclusion criteria were allocated to either ‘usual’ scalpel debridement or corn plaster treatment. All participants had measurements of corn size, pain using a 100 mm visual analogue scale (VAS) and health‐related quality of life (EQ‐5D) measures by an independent podiatrist, blind to treatment allocation at baseline, 3, 6, 9 and 12 months.

Results

202 participants were randomised to receive scalpel debridement or corn plaster treatment (101 in each group). At 3 months 34% (32/95) of corns had completely resolved in the corn plaster group compared with 21% (20/94) in the scalpel group (p = 0.044), and 83% (79/95) had reduced in size in the corn plaster group compared with 56% (53/94) in the scalpel group (p < 0.001). At 12 months, time to corn recurrence was longer in the corn plaster group (p < 0.001). Pain from the corns was significantly lower in the corn plaster group at 3 months (p < 0.001) and EQ‐5D scores changed (improved), from baseline, by 0.09 (SD ±0.31) and 0.01 (SD ±0.25) points in the corn plaster and scalpel groups respectively (p = 0.056). By month 12, EQ‐5D scores had changed by 0.12 and −0.05 in the corn plaster and scalpel groups respectively (p = 0.005). The EQ‐5D, VAS scores and the four domains of the Foot Disability Scale were similar in both groups at 3 and 12 months. The economic analysis indicated that corn plasters were a cost effective intervention.

Conclusions

The use of corn plasters was associated with a higher proportion of resolved corns, a prolonged time to corn recurrence, less pain and reduced corn size over the first 6 months in comparison with ‘usual’ scalpel treatment and this intervention was cost effective. Used under supervision of a podiatrist on appropriate patients, corn plasters offer an effective alternative to scalpel debridement.
A new intertidal Brachionus and intrageneric phylogenetic relationships among Brachionus as revealed by allometry and CO1-ITS1 gene analysis
Authors: Hwang Dae-Sik , Dahms Hans-Uwe , Park Heum Gi , Lee Jae-Seong
Published: September 2013

Background

The rotifer genus Brachionus is distributed worldwide along a gradient from freshwater to seawater habitats. This genus is recognized as a suitable organism for testing environmental and evolutionary hypotheses. Here we present the description of a new species and the phylogenetic relationship within the genus Brachionus as revealed by morphometric allometry of two representatives and CO1-ITS1 gene analysis of five representatives belonging to Brachionus distributed in the fresh and seawaters of Korea, Japan, and China.

Results

Similarities of populations were studied using nuclear rDNA ITS1 sequences from Brachionus spp. collected from different geographical areas of Far East Asia. The phylogeographic analysis of nuclear DNA ITS1 and mitochondrial CO1 sequences showed that Brachionus from South Korea formed five distinct clades according to their geographic origin. Interspecific differences suggest that Brachionus species established on conventional morphological characters also forms five separate clades. When ITS1-CO1 of the Asian specimens was compared with representatives of Brachionus worldwide, a high genotypic similarity was found. However, they slightly differed between localities.

Conclusions

This study sets a first step for an integrative morphological and molecular characterization of the diversity contained within the ecologically and economically important rotifer genus Brachionus.
Recircumscription of Begonia sect. Baryandra (Begoniaceae): evidence from molecular data
Authors: Rubite Rosario Rivera , Hughes Mark , Alejandro Grecebio JD , Peng Ching-I
Published: September 2013

Background

Begonia sect. Diploclinium is a ‘dust-bin’ section for species retaining pleisiomorphic characters and lacking novel synapomorphic characters used to delimit other Asian sections in Begonia. Part of this large and polymorphous section is transferred to Begonia sect. Baryandra in a move towards a more natural classification for the genus.

Results

Phylogenetic analysis of nuclear ribosomal ITS DNA sequences show a strongly supported monophyletic group containing Philippine and Bornean species previously in Begonia sect. Diploclinium, and the type of Begonia sect. Baryandra, B. oxysperma. This clade forms the basis for the now much-expanded Begonia sect. Baryandra, which as defined here contains 49 species and has its centre of diversity in the Philippines.

Conclusions

A natural classification for a much expanded Begonia sect. Baryandra has been provided. This paper highlights the feasibility of moving towards a natural classification of Asian Begonia step by step as information comes to light through building upon previous framework phylogenies with denser sampling.
Safety, tolerability, pharmacokinetics and pharmacodynamics of an anti- oncostatin M monoclonal antibody in rheumatoid arthritis: results from phase II randomized, placebo-controlled trials
Authors: Choy Ernest H , Bendit Marina , McAleer Dana , Liu Feng , Feeney Maria , Brett Sara , Zamuner Stefano , Campanile Andrea , Toso John
Published: September 2013

Introduction

Oncostatin M (OSM) has been implicated in the pathophysiology of rheumatoid arthritis (RA) through its effect on inflammation and joint damage. GSK315234 is a humanised anti-OSM Immunoglobulin G1 (IgG1) monoclonal antibody (mAb). This 3-part study examines the safety, tolerability and efficacy of GSK315234 in patients with active RA.

Method

This was a 3-part (Parts A, B and C), multicenter study. Part A and Part B were randomised, double-blind, placebo-controlled, Bayesian adaptive dose finding studies to investigate the safety, tolerability, efficacy, pharmacokinetics and pharmacodynamics of single (Part A) and 3 repeat (Part B) intravenous infusions of GSK315234 in patients with active RA on a background of methotrexate (MTX). Part C was a single dose, randomised, single-blind, placebo-controlled study to assess subcutaneously administered GSK315234 to patients with active RA on a background of MTX.

Result

The primary endpoint of the study was mean change in DAS28 at Day 28 in Part A and Day 56 in Part B and C. All patients receiving at least one dose of GSK315234 were included in safety analysis. In Part A, there were statistically significant differences in DAS28 between 3 mg/kg and placebo at Day 56, 84 and 91. There was also a statistically significant difference in DAS28 between 0.3 mg/kg, 3 mg/kg and 10 mg/kg, as compared to placebo, at Day 84. Although these changes were small and occurred late, they supported progression to Part B and C to determine the therapeutic potential of GSK315234. For Part B, no significant difference was observed between 6 mg/kg and placebo. For Part C, a statistically significant difference in DAS28 was observed at Day 40, Day 84 and Day 100 between the 500 mg subcutaneous group, as compared to placebo. No significant findings were observed at any of the time points for EULAR response criteria, ACR20, ACR50 or ACR70. An exploratory analysis of clinical, pharmacokinetic and pharmacodynamics data suggests the lack of efficacy may be due to moderate binding affinity and rapid off-rate of GSK315234 as compared to the higher affinity OSM receptor causing a protein carrier effect prolonging the half life of OSM due to accumulation of the OSM/antibody complex in the serum and synovial fluid.

Conclusion

Our data highlighted the importance of binding affinity and off-rate effect of a mAb to fully neutralize the target and how this may influence its efficacy and potentially worsen disease activity. Using an anti-OSM mAb with high affinity should test this hypothesis and examine the potential of OSM as a therapeutic target in RA.

Trial registration

ClinicalTrials.gov no: NCT00674635
Scavenger receptor class B type I regulates cellular cholesterol metabolism and cell signaling associated with breast cancer development
Authors: Danilo Christiane , Gutierrez-Pajares Jorge L , Mainieri Maria Antonietta , Mercier Isabelle , Lisanti Michael P , Frank Philippe G
Published: September 2013

Introduction

Previous studies have identified cholesterol as an important regulator of breast cancer development. High-density lipoprotein (HDL) and its cellular receptor, the scavenger receptor class B type I (SR-BI) have both been implicated in the regulation of cellular cholesterol homeostasis, but their functions in cancer remain to be established.

Methods

In the present study, we have examined the role of HDL and SR-BI in the regulation of cellular signaling pathways in breast cancer cell lines and in the development of tumor in a mouse xenograft model.

Results

Our data show that HDL is capable of stimulating migration and can activate signal transduction pathways in the two human breast cancer cell lines, MDA-MB-231 and MCF7. Furthermore, we also show that knockdown of the HDL receptor, SR-BI, attenuates HDL-induced activation of the phosphatidylinositol 3-kinase (PI3K)/protein Kinase B (Akt) pathway in both cell lines. Additional investigations show that inhibition of the PI3K pathway, but not that of the mitogen-activated protein kinase (MAPK) pathway, could lead to a reduction in cellular proliferation in the absence of SR-BI. Importantly, whereas the knockdown of SR-BI led to decreased proliferation and migration in vitro, it also led to a significant reduction in tumor growth in vivo. Most important, we also show that pharmacological inhibition of SR-BI can attenuate signaling and lead to decreased cellular proliferation in vitro. Taken together, our data indicate that both cholesteryl ester entry via HDL-SR-BI and Akt signaling play an essential role in the regulation of cellular proliferation and migration, and, eventually, tumor growth.

Conclusions

These results identify SR-BI as a potential target for the treatment of breast cancer.
Developing an early screening instrument for predicting psychological morbidity after critical illness
Authors: Schandl Anna , Bottai Matteo , Hellgren Elisabeth , Sundin Orjan , Sackey Peter V
Published: September 2013

Introduction

Guidelines recommend follow-up for patients after an intensive care unit (ICU) stay. Methods for identifying patients with psychological problems after intensive care would be of value, to optimize treatment and to improve adequate resource allocation in ICU follow-up of ICU survivors. The aim of the study was to develop a predictive screening instrument, for use at ICU discharge, to identify patients at risk for post-traumatic stress, anxiety or depression.

Methods

Twenty-one potential risk factors for psychological problems - patient characteristics and ICU-related variables - were prospectively collected at ICU discharge. Two months after ICU discharge 252 ICU survivors received the questionnaires Post-Traumatic Stress Symptom scale -10 (PTSS-10) and Hospital Anxiety and Depression Scale (HADS) to estimate the degree of post-traumatic stress, anxiety and depression.

Results

Of the 150 responders, 46 patients (31%) had adverse psychological outcome, defined as PTSS-10 >35 and/or HADS subscales ≥8. After analysis, six predictors were included in the screening instrument: major pre-existing disease, being a parent to children younger than 18 years of age, previous psychological problems, in-ICU agitation, being unemployed or on sick-leave at ICU admission and appearing depressed in the ICU. The total risk score was related to the probability for adverse psychological outcome in the individual patient. The predictive accuracy of the screening instrument, as assessed with area under the receiver operating characteristic curve, was 0.77. When categorizing patients in three risk probability groups - low (0 to 29%), moderate (30 to 59%) high risk (60 to 100%), the actual prevalence of adverse psychological outcome in respective groups was 12%, 50% and 63%.

Conclusion

The screening instrument developed in this study may aid ICU clinicians in identifying patients at risk for adverse psychological outcome two months after critical illness. Prior to wider clinical use, external validation is needed.
Endothelial Damage in Long-Term Survivors of Childhood Cancer
Authors: Brouwer Cornelia A.J. , Postma Aleida , Hooimeijer H. Louise H. , Smit Andries J. , Vonk Judith M. , van Roon Arie M. , van den Berg Maarten P. , Dolsma Wil V. , Lefrandt Joop D. , Bink-Boelkens Margreet T.E. , Zwart Nynke , de Vries Elisabeth G.E. , Tissing Wim J.E. , Gietema Jourik A.
Published: September 2013

Purpose

To evaluate the presence of vascular damage in long-term childhood cancer survivors (CCS) and sibling controls, and to evaluate the association between vascular damage parameters and cancer treatment and influence of cardiovascular risk factors.

Patients and Methods

Vascular assessment was performed in 277 adult CCSs (median age at diagnosis, 9 years; range, 0 to 20 years; median current age, 28 years; range, 18 to 48 years) treated with potentially cardiovascular toxic anticancer treatment (ie, anthracyclines, platinum, and/or radiotherapy [RT]). Measurements included carotid- and femoral-wall intima-media thickness (IMT), flow-mediated vasodilatation of the brachial artery by ultrasound, assessment of endothelial and inflammatory marker proteins (including tissue-type plasminogen activator [t-PA], plasminogen activator inhibitor type 1 [PAI-I]), and cardiovascular risk factors. CCS assessments were compared with those of 130 sibling controls (median age, 26 years; range, 18 to 51 years).

Results

At a median of 18 years (range, 5 to 31 years) after treatment, carotid and femoral IMTs in CCSs were not different from those of controls. However, CCSs who received RT as part of their treatment regimen had increased carotid and femoral IMTs and higher t-PA and PAI-I levels, indicating vascular damage and persistent endothelial activation. Patients treated with RT to the neck or chest also had greater femoral IMT. Greater IMT was associated with presence of cardiovascular risk factors (eg, hypertension and overweight).

Conclusion

After potentially cardiovascular toxic anticancer treatment, CCSs who received RT showed signs of endothelial damage and an unfavorable cardiovascular risk profile compared with controls. CCSs treated with localized RT had increased IMT outside the primary irradiation field. These abnormalities are probably involved in the pathogenesis of cardiovascular morbidity in CCSs.
Functional Decline in Older Patients With Cancer Receiving First-Line Chemotherapy
Authors: Hoppe Stéphanie , Rainfray Muriel , Fonck Marianne , Hoppenreys Laurent , Blanc Jean-Frédéric , Ceccaldi Joël , Mertens Cécile , Blanc-Bisson Christèle , Imbert Yves , Cany Laurent , Vogt Luc , Dauba Jérôme , Houédé Nadine , Bellera Carine A. , Floquet Anne , Fabry Marie-Noëlle , Ravaud Alain , Chakiba Camille , Mathoulin-Pélissier Simone , Soubeyran Pierre
Published: September 2013

Purpose

To determine factors associated with early functional decline during first-line chemotherapy in older patients.

Patients and Methods

Patients age ≥ 70 years receiving first-line chemotherapy for cancer were prospectively considered for inclusion across 12 centers in France. Functional decline was defined as a decrease of ≥ 0.5 points on the Activities of Daily Living (ADL) scale between the beginning of chemotherapy and the second cycle. Factors associated with functional decline were sought from pretreatment abbreviated comprehensive geriatric assessment, including ADL, Instrumental ADL (IADL), Mini-Nutritional Assessment (MNA), Mini–Mental State Examination (MMSE), Geriatric Depression Scale (GDS15), and Timed Get Up and Go (GUG) test, and from comorbidities (Cumulative Illness Rating Scale–Geriatrics), MAX2 index, and baseline biologic and clinical information.

Results

Of 364 included patients, 50 experienced functional decline (16.7%; median, 0.5 points). Abnormal preadmission performance status, IADL, GDS15, MMSE, GUG, and MNA were associated with increased likelihood of functional decline (univariate analysis). In the multivariate model adjusted for baseline ADL and MAX2 index, high baseline GDS (odds ratio [OR], 2.16; 95% CI, 1.09 to 4.30; P = .03) and low IADL scores (OR, 2.87; 95% CI, 1.06 to 7.79; P = .04) were independently associated with increased risk of functional decline.

Conclusion

Our results outline associations between baseline depression, instrumental dependencies, and early functional decline during chemotherapy for older patients. ADL should be sequentially evaluated early during treatment. Baseline evaluation of GDS15 and IADL may be proposed to anticipate this event.
Impact of Rituximab and Radiotherapy on Outcome of Patients With Aggressive B-Cell Lymphoma and Skeletal Involvement
Authors: Held Gerhard , Zeynalova Samira , Murawski Niels , Ziepert Marita , Kempf Barbara , Viardot Andreas , Dreyling Martin , Hallek Michael , Witzens-Harig Mathias , Fleckenstein Jochen , Rübe Christian , Zwick Carsten , Glass Bertram , Schmitz Norbert , Pfreundschuh Michael
Published: September 2013

Purpose

To study clinical presentation, outcome, and the role of radiotherapy in patients with aggressive B-cell lymphoma and skeletal involvement treated with and without rituximab.

Patients and Methods

Outcome of patients with skeletal involvement was analyzed in a retrospective study of nine consecutive prospective trials of the German High-Grade Non-Hodgkin lymphoma Study Group.

Results

Of 3,840 patients, 292 (7.6%) had skeletal involvement. In the MabThera International Trial (MInT) for young good-prognosis patients and the Rituximab With CHOP Over 60 Years (RICOVER-60) study for elderly patients, the randomized addition of rituximab improved event-free survival (EFS; hazard ratio for MInT [HRMInT] = 0.4, P > 001; hazard ratio for RICOVER-60 [HRRICOVER-60] = 0.6, P > .001) and overall survival (OS; HRMInT = 0.4, P < .001; HRRICOVER-60 = 0.7, P = .002) in patients without skeletal involvement, but failed to improve the outcome of patients with skeletal involvement (EFS: HRMInT = 1.4, P = .444; HRRICOVER-60 = 0.8, P = .449; OS: HRMInT = 0.6, P = .449; HRRICOVER-60 = 1.0, P = .935). Skeletal involvement was associated with a worse outcome after cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) plus rituximab (HREFS = 1.5, P = .048; HROS = 1.1; P = .828), but not after CHOP without rituximab (HREFS = 0.8, P = .181; HROS = 0.7, P = .083). In contrast to rituximab, additive radiotherapy to sites of skeletal involvement was associated with a decreased risk (HREFS = 0.3, P = .001; HROS = 0.5; P = .111).

Conclusion

Rituximab failed to improve the outcome of patients with diffuse large B-cell lymphoma with skeletal involvement, although our data suggest a beneficial effect of radiotherapy to sites of skeletal involvement. Whether radiotherapy to sites of skeletal involvement can be spared in cases with a negative positron emission tomography after immunochemotherapy should be addressed in appropriately designed prospective trials.
Marital Status and Survival in Patients With Cancer
Authors: Aizer Ayal A. , Chen Ming-Hui , McCarthy Ellen P. , Mendu Mallika L. , Koo Sophia , Wilhite Tyler J. , Graham Powell L. , Choueiri Toni K. , Hoffman Karen E. , Martin Neil E. , Hu Jim C. , Nguyen Paul L.
Published: September 2013

Purpose

To examine the impact of marital status on stage at diagnosis, use of definitive therapy, and cancer-specific mortality among each of the 10 leading causes of cancer-related death in the United States.

Methods

We used the Surveillance, Epidemiology and End Results program to identify 1,260,898 patients diagnosed in 2004 through 2008 with lung, colorectal, breast, pancreatic, prostate, liver/intrahepatic bile duct, non-Hodgkin lymphoma, head/neck, ovarian, or esophageal cancer. We used multivariable logistic and Cox regression to analyze the 734,889 patients who had clinical and follow-up information available.

Results

Married patients were less likely to present with metastatic disease (adjusted odds ratio [OR], 0.83; 95% CI, 0.82 to 0.84; P < .001), more likely to receive definitive therapy (adjusted OR, 1.53; 95% CI, 1.51 to 1.56; P < .001), and less likely to die as a result of their cancer after adjusting for demographics, stage, and treatment (adjusted hazard ratio, 0.80; 95% CI, 0.79 to 0.81; P < .001) than unmarried patients. These associations remained significant when each individual cancer was analyzed (P < .05 for all end points for each malignancy). The benefit associated with marriage was greater in males than females for all outcome measures analyzed (P < .001 in all cases). For prostate, breast, colorectal, esophageal, and head/neck cancers, the survival benefit associated with marriage was larger than the published survival benefit of chemotherapy.

Conclusion

Even after adjusting for known confounders, unmarried patients are at significantly higher risk of presentation with metastatic cancer, undertreatment, and death resulting from their cancer. This study highlights the potentially significant impact that social support can have on cancer detection, treatment, and survival.
Phase II Trial of Palliative Radiotherapy for Hepatocellular Carcinoma and Liver Metastases
Authors: Soliman Hany , Ringash Jolie , Jiang Haiyan , Singh Kawalpreet , Kim John , Dinniwell Robert , Brade Anthony , Wong Rebecca , Brierley James , Cummings Bernard , Zimmermann Camilla , Dawson Laura A.
Published: September 2013

Purpose

To evaluate the feasibility and response of liver radiotherapy (RT) in improving symptoms and quality of life in patients with hepatocellular carcinoma (HCC) or liver metastases (LM).

Patients and Methods

Eligible patients had HCC or LM, unsuitable for or refractory to standard therapies, with an index symptom of pain, abdominal discomfort, nausea, or fatigue. The Brief Pain Inventory (BPI), Functional Assessment of Cancer Therapy–Hepatobiliary (FACT-Hep), and European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C30 (EORTC QLQ-C30) were completed by patients at baseline and each follow-up. The primary outcome was the percentage of patients with a clinically significant change at 1 month in the BPI subscale of symptom on average in the past 24 hours. Secondary outcomes were improvement in other BPI subscales and at other time points, FACT-Hep and EORTC QLQ-C30 at each follow-up, and toxicity at 1 week.

Results

Forty-one patients (30 men and 11 women) with HCC (n = 21) or LM (n = 20) were accrued. At 1 month, 48% had an improvement in symptom on average in the past 24 hours. Fifty-two percent of patients had improvement in symptom at its worst, 37% at its least, and 33% now. Improvements in the FACT-G and hepatobiliary subscale were seen in 23% and 29% of patients, respectively, at 1 month. There were also improvements in EORTC QLQ-C30 functional (range, 11% to 21%) and symptom (range, 11% to 50%) domains. One patient developed grade 3 nausea at 1 week.

Conclusion

Improvements in symptoms were observed at 1 month in a substantial proportion of patients. A phase III study of palliative liver RT is planned.
On the Performance of the U.S. Transportation System: Caution Ahead
Authors: Winston Clifford
Published: September 2013

Transportation is a vital sector of the U.S. economy based on consumers', firms', and government's enormous expenditures in money and time and on its effect on virtually all other sectors in the economy. I assess the performance of the transportation system and consider how it could be improved by analyzing whether the United States has the optimal mix of public and private provision. The empirical evidence indicates that our hugely important transportation system has been compromised by various government policies and the significant welfare costs motivate either vastly improving public provision or expanding the role of the private sector. (JEL H44, H54, H76, L91, L98, R41, R48)
FMRP regulates actin filament organization via the armadillo protein p0071
Authors: Nolze Alexander , Schneider Jacqueline , Keil René , Lederer Marcell , Hüttelmaier Stefan , Kessels Michael M. , Qualmann Britta , Hatzfeld Mechthild
Published: September 2013

Loss of fragile X mental retardation protein (FMRP) causes synaptic dysfunction and intellectual disability. FMRP is an RNA-binding protein that controls the translation or turnover of a subset of mRNAs. Identifying these target transcripts is an important step toward understanding the pathology of the disease. Here, we show that FMRP regulates actin organization and neurite outgrowth via the armadillo protein p0071. In mouse embryonic fibroblasts (MEFs) lacking FMRP (Fmr1−), the actin cytoskeleton was markedly reorganized with reduced stress fibers and F-actin/G-actin ratios compared to fibroblasts re-expressing the protein. FMRP interfered with the translation of the p0071 mRNA in a 3′-UTR-dependent manner. Accordingly, FMRP-depleted cells revealed elevated levels of p0071 protein. The knockdown of p0071 in Fmr1− fibroblasts restored stress fibers and an elongated cell shape, thus rescuing the Fmr1− phenotype, whereas overexpression of p0071 in Fmr1+ cells mimicked the Fmr1− phenotype. Moreover, p0071 and FMRP regulated neurite outgrowth and branching in a diametrically opposed way in agreement with the negative regulation of p0071 by FMRP. These results identify p0071 as an important and novel FMRP target and strongly suggest that impaired actin cytoskeletal functions mediated by an excess of p0071 are key aspects underlying the fragile X syndrome.
MicroRNAs act complementarily to regulate disease-related mRNA modules in human diseases
Authors: Chavali Sreenivas , Bruhn Sören , Tiemann Katrin , Sætrom Pål , Barrenäs Fredrik , Saito Takaya , Kanduri Kartiek , Wang Hui , Benson Mikael
Published: September 2013

MicroRNAs (miRNAs) play a key role in regulating mRNA expression, and individual miRNAs have been proposed as diagnostic and therapeutic candidates. The identification of such candidates is complicated by the involvement of multiple miRNAs and mRNAs as well as unknown disease topology of the miRNAs. Here, we investigated if disease-associated miRNAs regulate modules of disease-associated mRNAs, if those miRNAs act complementarily or synergistically, and if single or combinations of miRNAs can be targeted to alter module functions. We first analyzed publicly available miRNA and mRNA expression data for five different diseases. Integrated target prediction and network-based analysis showed that the miRNAs regulated modules of disease-relevant genes. Most of the miRNAs acted complementarily to regulate multiple mRNAs. To functionally test these findings, we repeated the analysis using our own miRNA and mRNA expression data from CD4+ T cells from patients with seasonal allergic rhinitis. This is a good model of complex diseases because of its well-defined phenotype and pathogenesis. Combined computational and functional studies confirmed that miRNAs mainly acted complementarily and that a combination of two complementary miRNAs, miR-223 and miR-139-3p, could be targeted to alter disease-relevant module functions, namely, the release of type 2 helper T-cell (Th2) cytokines. Taken together, our findings indicate that miRNAs act complementarily to regulate modules of disease-related mRNAs and can be targeted to alter disease-relevant functions.
Thermodynamic contribution and nearest-neighbor parameters of pseudouridine-adenosine base pairs in oligoribonucleotides
Authors: Hudson Graham A. , Bloomingdale Richard J. , Znosko Brent M.
Published: September 2013

Pseudouridine (Ψ) is the most common noncanonical nucleotide present in naturally occurring RNA and serves a variety of roles in the cell, typically appearing where structural stability is crucial to function. Ψ residues are isomerized from native uridine residues by a class of highly conserved enzymes known as pseudouridine synthases. In order to quantify the thermodynamic impact of pseudouridylation on U-A base pairs, 24 oligoribonucleotides, 16 internal and eight terminal Ψ-A oligoribonucleotides, were thermodynamically characterized via optical melting experiments. The thermodynamic parameters derived from two-state fits were used to generate linearly independent parameters for use in secondary structure prediction algorithms using the nearest-neighbor model. On average, internally pseudouridylated duplexes were 1.7 kcal/mol more stable than their U-A counterparts, and terminally pseudouridylated duplexes were 1.0 kcal/mol more stable than their U-A equivalents. Due to the fact that Ψ-A pairs maintain the same Watson-Crick hydrogen bonding capabilities as the parent U-A pair in A-form RNA, the difference in stability due to pseudouridylation was attributed to two possible sources: the novel hydrogen bonding capabilities of the newly relocated imino group as well as the novel stacking interactions afforded by the electronic configuration of the Ψ residue. The newly derived nearest-neighbor parameters for Ψ-A base pairs may be used in conjunction with other nearest-neighbor parameters for accurately predicting the most likely secondary structure of A-form RNA containing Ψ-A base pairs.
Bicaudal-C spatially controls translation of vertebrate maternal mRNAs
Authors: Zhang Yan , Cooke Amy , Park Sookhee , Dewey Colin N. , Wickens Marvin , Sheets Michael D.
Published: September 2013

The Xenopus Cripto-1 protein is confined to the cells of the animal hemisphere during early embryogenesis where it regulates the formation of anterior structures. Cripto-1 protein accumulates only in animal cells because cripto-1 mRNA in cells of the vegetal hemisphere is translationally repressed. Here, we show that the RNA binding protein, Bicaudal-C (Bic-C), functioned directly in this vegetal cell-specific repression. While Bic-C protein is normally confined to vegetal cells, ectopic expression of Bic-C in animal cells repressed a cripto-1 mRNA reporter and associated with endogenous cripto-1 mRNA. Repression by Bic-C required its N-terminal domain, comprised of multiple KH motifs, for specific binding to relevant control elements within the cripto-1 mRNA and a functionally separable C-terminal translation repression domain. Bic-C-mediated repression required the 5′ CAP and translation initiation factors, but not a poly(A) tail or the conserved SAM domain within Bic-C. Bic-C-directed immunoprecipitation followed by deep sequencing of associated mRNAs identified multiple Bic-C-regulated mRNA targets, including cripto-1 mRNA, providing new insights and tools for understanding the role of Bic-C in vertebrate development.
Novel targets of miR-30, a microRNA required for biliary development
Authors: Le Guen Claire L. , Friedman Joshua R. , Hand Nicholas J.
Published: September 2013

MicroRNAs have been found to play a profound role in embryonic and post-natal development through their regulation of processes such as cell proliferation, differentiation, and morphogenesis. The microRNA-30 (miR-30) family is necessary for vertebrate hepatobiliary development; however, the mechanism through which miR-30 regulates these processes is not fully understood. Here, we identify genes directly regulated by miR-30 that have been characterized as key developmental factors. The targets were confirmed via a luciferase reporter assay, following exogenous over-expression of miR-30a and miR-30c2 in cultured cells. Five novel miR-30ac2 targets were identified using this approach, all of which play crucial roles in hepatobiliary development or are involved in hepatocellular carcinoma and cholangiocarcinoma.
Pesquisa Ergológica: cientificidade, coerência, paradigma e articulação conceitual
Authors: Holz Edvalter Becker
Published: September 2013

DOI: http://dx.doi.org/10.13071/regec.2317-5087.2013.2.1.4447.210-230.Trata-se de um ensaio teórico que apresenta quatro pontos carentes de reflexão e aprofundamento na literatura ergológica: cientificidade, coerência, paradigmatização e articulação conceitual. Os pontos são apresentados em forma de questionamentos principais, a partir dos quais se desdobram reflexões e novos questionamentos. O ensaio não busca respostas prontas e fechadas e não tem a pretensão de se constituir um resumo, mas se apoia em devido e coerente aporte teórico. É um trabalho relevante para os Estudos Organizacionais, uma vez que a Ergologia vem sendo utilizada por pesquisadores desta área, mas sem dirigir-se especificamente a ela, pois se trata de uma abordagem pluridisciplinar. Traz elucidações importantes, porém com intuito de gerar novos questionamentos e reforçar a necessidade de aprofundamento sobre as mesmas. Assim, as considerações finais não são propriamente conclusivas, reforçando a necessidade de cuidado epistemológico, mas ressaltando o lado inantecipável da abordagem.
Percepção e Fidelização: um estudo dos clientes de farmácias na cidade de Vitória (ES)
Authors: Gabriel Mikaelli Orlande , Pelissari Anderson Soncini , Oliveira Marcos Paulo Valadares de
Published: September 2013

DOI: http://dx.doi.org/10.13071/regec.2317-5087.2013.2.1.4460.187-209.Para lidar com as inúmeras mudanças sofridas pelo setor, as empresas do mercado varejista farmacêutico têm como alternativa a oferta amplificada de serviços com maior qualidade, e o desenvolvimento de relacionamentos longos com seus clientes. Este trabalho analisa a percepção do cliente quanto ao serviço prestado pelas farmácias, bem como aspectos relacionados à fidelização dos clientes do varejo farmacêutico. Para tanto, realizou-se uma pesquisa com aplicação de questionários em uma amostra do tipo não probabilística por cotas (faixa etária e região), de 196 clientes de farmácias localizadas em Vitória, ES. O tratamento dos dados foi feito através dos softwares EXCEL e SPSS. Verificou-se que os aspectos preço baixo e localização da farmácia são os mais relevantes para clientes fiéis e não fiéis. Concluiu-se ainda que os cartões-fidelidade podem ser uma estratégia utilizada pelas empresas para agregar valor ao seu negócio, mas não podem ser um indicador ou instrumento de fidelização.
O Melhoramento Genético de Cana-de-Açúcar no Brasil e o Desafio das Mudanças Climáticas Globais
Authors: Carvalho Silvia Angélica Domingues de , Furtado Andre Tosi
Published: September 2013

DOI: http://dx.doi.org/10.13071/regec.2317-5087.2013.2.1.4909.22-46.Diante dos desafios colocados pelas mudanças climáticas, o Brasil precisa promover o crescimento sustentado da produção de cana-de-açúcar para atender à crescente demanda. A expansão da produção depende do desenvolvimento de variedades adaptadas ao solo e ao clima das novas áreas de expansão. O setor sucroalcooleiro nacional possui instituições historicamente responsáveis pelos avanços no desenvolvimento tecnológico e de inovação no setor. Então, identificar os principais desafios tecnológicos que essas instituições, em seus programas de melhoramento, têm encontrado é vital para o Brasil manter a liderança na produção de cana-de-açúcar. Nesta pesquisa, verificou-se que, apesar dos recursos tecnológicos existentes, os desafios colocados pelas novas condições climáticas e as mudanças na regulamentação setorial impõem limitações que devem ser superadas: o tempo de colocação de uma variedade no mercado; as dificuldades de infraestrutura interna; as dificuldades na transmissão de conhecimentos aos produtores; a falta de apoio do governo; a complexidade genética de cana-planta; entre outros.