bluuebunny/crossref_metadata_2025_split huggingface dataset:
Growth regulation of simian and human AIDS-related non-Hodgkin's lymphoma cell lines by TGF-β1 and IL-6
Authors: Ruff Kristin R , Puetter Adriane , Levy Laura S 
Published: February 2007

Abstract

Background
AIDS-related non-Hodgkin's lymphoma (AIDS-NHL) is the second most frequent cancer associated with AIDS, and is a frequent cause of death in HIV-infected individuals. Experimental analysis of AIDS-NHL has been facilitated by the availability of an excellent animal model, i.e., simian Acquired Immunodeficiency Syndrome (SAIDS) in the rhesus macaque consequent to infection with simian immunodeficiency virus. A recent study of SAIDS-NHL demonstrated a lymphoma-derived cell line to be sensitive to the growth inhibitory effects of the ubiquitous cytokine, transforming growth factor-beta (TGF-beta). The authors concluded that TGF-beta acts as a negative growth regulator of the lymphoma-derived cell line and, potentially, as an inhibitory factor in the regulatory network of AIDS-related lymphomagenesis. The present study was conducted to assess whether other SAIDS-NHL and AIDS-NHL cell lines are similarly sensitive to the growth inhibitory effects of TGF-beta, and to test the hypothesis that interleukin-6 (IL-6) may represent a counteracting positive influence in their growth regulation.

Methods
Growth stimulation or inhibition in response to cytokine treatment was quantified using trypan blue exclusion or colorimetric MTT assay. Intracellular flow cytometry was used to analyze the activation of signaling pathways and to examine the expression of anti-apoptotic proteins and distinguishing hallmarks of AIDS-NHL subclass. Apoptosis was quantified by flow cytometric analysis of cell populations with sub-G1 DNA content and by measuring activated caspase-3.

Results
Results confirmed the sensitivity of LCL8664, an immunoblastic SAIDS-NHL cell line, to TGF-beta1-mediated growth inhibition, and further demonstrated the partial rescue by simultaneous treatment with IL-6. IL-6 was shown to activate STAT3, even in the presence of TGF-beta1, and thereby to activate proliferative and anti-apoptotic pathways. By comparison, human AIDS-NHL cell lines differed in their responsiveness to TGF-beta1 and IL-6. Analysis of a recently derived AIDS-NHL cell line, UMCL01-101, indicated that it represents immunoblastic AIDS-DLCBL. Like LCL-8664, UMCL01-101 was sensitive to TGF-beta1-mediated inhibition, rescued partially by IL-6, and demonstrated rapid STAT3 activation following IL-6 treatment even in the presence of TGF-beta1.

Conclusion
These studies indicate that the sensitivity of immunoblastic AIDS- or SAIDS-DLBCL to TGF-beta1-mediated growth inhibition may be overcome through the stimulation of proliferative and anti-apoptotic signals by IL-6, particularly through the rapid activation of STAT3.
Eruptive papules during efalizumab (anti-CD11a) therapy of psoriasis vulgaris: a case series
Authors: Lowes Michelle A , Chamian Francesca , Abello Maria V , Leonardi Craig , Dummer Wolfgang , Papp Kim , Krueger James G 
Published: February 2007

Abstract

Background
Newer biological therapies for moderate-to-severe psoriasis are being used more frequently, but unexpected effects may occur.

Case presentations
We present a group of 15 patients who developed inflammatory papules while on efalizumab therapy (Raptiva, Genentech Inc, anti-CD11a). Immunohistochemistry showed that there were increased CD11b+, CD11c+ and iNOS+ cells (myeloid leukocytes) in the papules, with relatively few CD3+ T cells. While efalizumab caused a decreased expression of CD11a on T cells, other circulating leukocytes from patients receiving this therapy often showed increased CD11b and CD11c. In the setting of an additional stimulus such as skin trauma, this may predispose to increased trafficking into the skin using these alternative β2 integrins. In addition, there may be impaired immune synapse formation, limiting the development of these lesions to small papules. There is little evidence for these papular lesions being "allergic" in nature as there are few eosinophils on biopsy, and they respond to minimal or no therapy even if efalizumab is continued.

Conclusion
We hypothesize that these papules may represent a unique type of "mechanistic" inflammatory reaction, seen only in the context of drug-induced CD11a blockade, and not during the natural disease process.
Expression, intracellular targeting and purification of HIV Nef variants in tobacco cells
Authors: Marusic Carla , Nuttall James , Buriani Giampaolo , Lico Chiara , Lombardi Raffaele , Baschieri Selene , Benvenuto Eugenio , Frigerio Lorenzo 
Published: February 2007

Abstract

Background
Plants may represent excellent alternatives to classical heterologous protein expression systems, especially for the production of biopharmaceuticals and vaccine components. Modern vaccines are becoming increasingly complex, with the incorporation of multiple antigens. Approaches towards developing an HIV vaccine appear to confirm this, with a combination of candidate antigens. Among these, HIV-Nef is considered a promising target for vaccine development because immune responses directed against this viral protein could help to control the initial steps of viral infection and to reduce viral loads and spreading. Two isoforms of Nef protein can be found in cells: a full-length N-terminal myristoylated form (p27, 27 kDa) and a truncated form (p25, 25 kDa). Here we report the expression and purification of HIV Nef from transgenic tobacco.

Results
We designed constructs to direct the expression of p25 and p27 Nef to either the cytosol or the secretory pathway. We tested these constructs by transient expression in tobacco protoplasts. Cytosolic Nef polypeptides are correctly synthesised and are stable. The same is not true for Nef polypeptides targeted to the secretory pathway by virtue of a signal peptide. We therefore generated transgenic plants expressing cytosolic, full length or truncated Nef. Expression levels were variable, but in some lines they averaged 0.7% of total soluble proteins. Hexahistidine-tagged Nef was easily purified from transgenic tissue in a one-step procedure.

Conclusion
We have shown that transient expression can help to rapidly determine the best cellular compartment for accumulation of a recombinant protein. We have successfully expressed HIV Nef polypeptides in the cytosol of transgenic tobacco plants. The proteins can easily be purified from transgenic tissue.
Design of a retrospective patient record study on the occurrence of adverse events among patients in Dutch hospitals
Authors: Zegers Marieke , de Bruijne Martine C , Wagner Cordula , Groenewegen Peter P , Waaijman Roelof , van der Wal Gerrit 
Published: February 2007

Abstract
Background
Various international studies have shown that a substantial number of patients suffer from injuries or even die as a result of care delivered in hospitals. The occurrence of injuries among patients caused by health care management in Dutch hospitals has never been studied systematically. Therefore, an epidemiological study was initiated to determine the incidence, type and impact of adverse events among discharged and deceased patients in Dutch hospitals.

Methods/Design
Three stage retrospective patient record review study in 21 hospitals of 8400 patient records of discharged or deceased patients in 2004. The records were reviewed by trained nurses and physicians between August 2005 and October 2006. In addition to the determination of presence, the degree of preventability, and causes of adverse events, also location, timing, classification, and most responsible specialty of the adverse events were measured. Moreover, patient and admission characteristics and the quality of the patient records were recorded.

Discussion
In this paper we report on the design of the retrospective patient record study on the occurrence of adverse events in Dutch hospitals. Attention is paid to the strengths and limitations of the study design. Furthermore, alterations made in the original research protocol in comparison with former international studies are described in detail.
Randomised controlled trial of a psychiatric consultation model for treatment of common mental disorder in the occupational health setting
Authors: van der Feltz-Cornelis Christina M , Meeuwissen Jolanda AC , de Jong Fransina J , Hoedeman Rob , Elfeddali Iman 
Published: February 2007

Abstract
Background
Common mental disorders are the most prevalent of all mental disorders, with the highest burden in terms of work absenteeism and utilization of health care services. Evidence-based treatments are available, but recognition and treatment could be improved, especially in the occupational health setting. The situation in this setting has recently changed in the Netherlands because of new legislation, which has resulted in reduced sickness absence. Severe mental disorder has now become one of the main causes of work absenteeism. Occupational physicians (OPs) are expected to take an active role in diagnosis and treatment, and seem to be in need of support for a new approach to handle cases of more complex mental disorders. Psychiatric consultation can be a collaborative care model to achieve this.

Methods/design
This is a two-armed cluster-randomized clinical trial, with randomization among OPs. Forty OPs in two big companies providing medical care for multiple companies will be randomized to either the intervention group, i.e. psychiatric consultation embedded in a training programme, or the control group, i.e. only training aimed at recognition and providing Care As Usual. 60 patients will be included who have been absent from work for 6–52 weeks and who, after screening and a MINI interview, are diagnosed with depressive disorder, anxiety disorder or somatoform disorder based on DSM-IV criteria. Baseline measurements and follow up measurements (at 3 months and 6 months) will be assessed with questionnaires and an interview. The primary outcome measure is level of general functioning according to the SF-20. Secondary measures are severity of the mental disorder according to the PHQ and the SCL-90, quality of life (EQ-D5), measures of Return To Work and cost-effectiveness of the treatment assessed with the TiC-P. Process measures will be adherence to the treatment plan and assessment of the treatment provided by the Psychiatric Consultant (PC) in both groups.

Discussion
In the current study, a psychiatric consultation model that has already proved to be effective in the primary care setting, and aimed to enhance evidence-based care for patients with work absenteeism and common mental disorder will be evaluated for its efficacy and cost-effectiveness in the occupational health setting.
The role of regulation in influencing income-generating activities among public sector doctors in Peru
Authors: Jumpa Manuel , Jan Stephen , Mills Anne 
Published: February 2007

Abstract

Objective
To examine in Peru the nature of dual practice (doctors holding two jobs at once – usually public sector doctors with private practices), the factors that influence individuals' decisions to undertake dual practice, the conditions faced when doing so and the potential role of regulatory intervention in this area.

Methods
The study entailed qualitative interviews with a sample of twenty medical practitioners based in metropolitan Lima, representing a cross-section of those primarily employed in either the private or public sectors and engaged in clinical practice or policy making. The interviews focused on:

individuals' experience with dual practice;

the general underlying pressures that influence the nature and extent of such activities; and

attitudes toward, and the influence of, regulation on such activities.

Results
Dual practice is an activity that is widespread and well-accepted, and the prime personal motivation is financial. However, there are also a number of important broad macroeconomic influences on dual practice particularly the oversupply of medical services, the deregulated nature of this market, and the economic crisis throughout the country, which combine to create major hardships for those attempting to make a living through medical practice. There is some support among doctors for tighter regulation.

Conclusion
Research findings suggest appropriate policy responses to dual practice involve tighter controls on the supply of medical practitioners; alleviation of financial pressures brought by macro-economic conditions; and closer regulation of such activities to ensure some degree of collective action over quality and the maintenance of professional reputations. Further research into this issue in rural areas is needed to ascertain the geographical generalizability of these policy responses.
FBXW7/hCDC4 controls glioma cell proliferation in vitro and is a prognostic marker for survival in glioblastoma patients
Authors: Hagedorn Martin , Delugin Maylis , Abraldes Isabelle , Allain Nathalie , Belaud-Rotureau Marc-Antoine , Turmo Michelle , Prigent Claude , Loiseau Hugues , Bikfalvi Andréas , Javerzat Sophie 
Published: February 2007

Abstract

Background
In the quest for novel molecular mediators of glioma progression, we studied the regulation of FBXW 7 (hCDC 4/hAGO/SEL 10), its association with survival of patients with glioblastoma and its potential role as a tumor suppressor gene in glioma cells. The F-box protein Fbxw7 is a component of SCFFbxw7, a Skp1-Cul1-F-box E3 ubiquitin ligase complex that tags specific proteins for proteasome degradation. FBXW 7 is mutated in several human cancers and functions as a haploinsufficient tumor suppressor in mice. Any of the identified targets, Cyclin E, c-Myc, c-Jun, Notch1/4 and Aurora-A may have oncogenic properties when accumulated in tumors with FBXW 7 loss.

Results
We tested the expression of FBXW 7 in human glioma biopsies by quantitative PCR and compared the transcript levels of grade IV glioma (glioblastoma, G-IV) with those of grade II tumors (G-II). In more than 80% G-IV, expression of FBXW 7 was significantly reduced. In addition, levels of FBXW 7 were correlated with survival indicating a possible implication in tumor aggressiveness. Locus 4q31.3 which carries FBXW 7 was investigated by in situ hybridization on biopsy touchprints. This excluded allelic loss as the principal cause for low expression of FBXW 7 in G-IV tumors. Two targets of Fbxw7, Aurora-A and Notch4 were preferentially immunodetected in G-IV biopsies. Next, we investigated the effects of FBXW 7 misregulation in glioma cells. U87 cells overexpressing nuclear isoforms of Fbxw7 lose the expression of the proliferation markers PCNA and Ki-67, and get counterselected in vitro. This observation fits well with the hypothesis that Fbxw7 functions as a tumor suppressor in astroglial cells. Finally, FBXW 7 knockdown in U87 cells leads to defects in mitosis that may promote aneuploidy in progressing glioma.

Conclusion
Our results show that FBXW 7 expression is a prognostic marker for patients with glioblastoma. We suggest that loss of FBXW 7 plays an important role in glioma malignancy by allowing the accumulation of multiple oncoproteins and that interfering with Fbxw7 or its downstream targets would constitute a new therapeutic advance.
A network perspective on the evolution of metabolism by gene duplication
Authors: Díaz-Mejía Juan Javier , Pérez-Rueda Ernesto , Segovia Lorenzo 
Published: February 2007

Abstract
Background
Gene duplication followed by divergence is one of the main sources of metabolic versatility. The patchwork and stepwise models of metabolic evolution help us to understand these processes, but their assumptions are relatively simplistic. We used a network-based approach to determine the influence of metabolic constraints on the retention of duplicated genes.

Results
We detected duplicated genes by looking for enzymes sharing homologous domains and uncovered an increased retention of duplicates for enzymes catalyzing consecutive reactions, as illustrated by the ligases acting in the biosynthesis of peptidoglycan. As a consequence, metabolic networks show a high retention of duplicates within functional modules, and we found a preferential biochemical coupling of reactions that partially explains this bias. A similar situation was found in enzyme-enzyme interaction networks, but not in interaction networks of non-enzymatic proteins or gene transcriptional regulatory networks, suggesting that the retention of duplicates results from the biochemical rules governing substrate-enzyme-product relationships. We confirmed a high retention of duplicates between chemically similar reactions, as illustrated by fatty-acid metabolism. The retention of duplicates between chemically dissimilar reactions is, however, also greater than expected by chance. Finally, we detected a significant retention of duplicates as groups, instead of single pairs.

Conclusion
Our results indicate that in silico modeling of the origin and evolution of metabolism is improved by the inclusion of specific functional constraints, such as the preferential biochemical coupling of reactions. We suggest that the stepwise and patchwork models are not independent of each other: in fact, the network perspective enables us to reconcile and combine these models.
RNA-editing-mediated exon evolution
Authors: Lev-Maor Galit , Sorek Rotem , Levanon Erez Y , Paz Nurit , Eisenberg Eli , Ast Gil 
Published: February 2007

Abstract
Background
Alu retroelements are specific to primates and abundant in the human genome. Through mutations that create functional splice sites within intronic Alus, these elements can become new exons in a process denoted exonization. It was recently shown that Alu elements are also heavily changed by RNA editing in the human genome.

Results
Here we show that the human nuclear prelamin A recognition factor contains a primate-specific Alu-exon that exclusively depends on RNA editing for its exonization. We demonstrate that RNA editing regulates the exonization in a tissue-dependent manner, through both the creation of a functional AG 3' splice site, and alteration of functional exonic splicing enhancers within the exon. Furthermore, a premature stop codon within the Alu-exon is eliminated by an exceptionally efficient RNA editing event. The sequence surrounding this editing site is important not only for editing of that site but also for editing in other neighboring sites as well.

Conclusion
Our results show that the abundant RNA editing of Alu sequences can be recruited as a mechanism supporting the birth of new exons in the human genome.
Gene Expression Signature in Advanced Colorectal Cancer Patients Select Drugs and Response for the Use of Leucovorin, Fluorouracil, and Irinotecan
Authors: Del Rio Maguy , Molina Franck , Bascoul-Mollevi Caroline , Copois Virginie , Bibeau Frédéric , Chalbos Patrick , Bareil Corinne , Kramar Andrew , Salvetat Nicolas , Fraslon Caroline , Conseiller Emmanuel , Granci Virginie , Leblanc Benjamin , Pau Bernard , Martineau Pierre , Ychou Marc 
Published: February 2007

Purpose In patients with advanced colorectal cancer, leucovorin, fluorouracil, and irinotecan (FOLFIRI) is considered as one of the reference first-line treatments. However, only about half of treated patients respond to this regimen, and there is no clinically useful marker that predicts response. A major clinical challenge is to identify the subset of patients who could benefit from this chemotherapy. We aimed to identify a gene expression profile in primary colon cancer tissue that could predict chemotherapy response. Patients and Methods Tumor colon samples from 21 patients with advanced colorectal cancer were analyzed for gene expression profiling using Human Genome GeneChip arrays U133. At the end of the first-line treatment, the best observed response, according to WHO criteria, was used to define the responders and nonresponders. Discriminatory genes were first selected by the significance analysis of microarrays algorithm and the area under the receiver operating characteristic curve. A predictor classifier was then constructed using support vector machines. Finally, leave-one-out cross validation was used to estimate the performance and the accuracy of the output class prediction rule. Results We determined a set of 14 predictor genes of response to FOLFIRI. Nine of nine responders (100% specificity) and 11 of 12 nonresponders (92% sensitivity) were classified correctly, for an overall accuracy of 95%. Conclusion After validation in an independent cohort of patients, our gene signature could be used as a decision tool to assist oncologists in selecting colorectal cancer patients who could benefit from FOLFIRI chemotherapy, both in the adjuvant and the first-line metastatic setting.
Direct Intracerebral Delivery of Cintredekin Besudotox (IL13-PE38QQR) in Recurrent Malignant Glioma: A Report by the Cintredekin Besudotox Intraparenchymal Study Group
Authors: Kunwar Sandeep , Prados Michael D. , Chang Susan M. , Berger Mitchel S. , Lang Frederick F. , Piepmeier Joseph M. , Sampson John H. , Ram Zvi , Gutin Philip H. , Gibbons Robert D. , Aldape Kenneth D. , Croteau David J. , Sherman Jeffrey W. , Puri Raj K. 
Published: February 2007

Purpose Glioblastoma multiforme (GBM) is a devastating brain tumor with a median survival of 6 months after recurrence. Cintredekin besudotox (CB) is a recombinant protein consisting of interleukin-13 (IL-13) and a truncated form of Pseudomonas exotoxin (PE38QQR). Convection-enhanced delivery (CED) is a locoregional-administration method leading to high-tissue concentrations with large volume of distributions. We assessed the use of intracerebral CED to deliver CB in patients with recurrent malignant glioma (MG). Patients and Methods Three phase I clinical studies evaluated intracerebral CED of CB along with tumor resection. The main objectives were to assess the tolerability of various concentrations and infusion durations; tissue distribution; and methods for optimizing delivery. All patients underwent tumor resection followed by a single intraparenchymal infusion (in addition to the intraparenchymal one following resection), with a portion of patients who had a preresection intratumoral infusion. Results A total of 51 patients with MG were treated including 46 patients with GBM. The maximum tolerated intraparenchymal concentration was 0.5 μg/mL and tumor necrosis was observed at this concentration. Infusion durations of up to 6 days were well tolerated. Postoperative catheter placement appears to be important for optimal drug distribution. CB- and procedure-related adverse events were primarily limited to the CNS. Overall median survival for GBM patients is 42.7 weeks and 55.6 weeks for patients with optimally positioned catheters with patient follow-up extending beyond 5 years. Conclusion CB appears to have a favorable risk-benefit profile. CED is a complex delivery method requiring catheter placement via a second procedure to achieve accurate catheter positioning, better drug distribution, and better outcome.