bluuebunny/crossref_metadata_2025 huggingface dataset:
A Continuous Approach to the Aeroelastic Stability of Suspended Cables in 1 : 2 Internal Resonance
Authors: Luongo A. , Piccardo G.
Published: January 2008

This paper proposes a continuous perturbation treatment of the nonlinear equations of a cable, which is characterized by possible aeroelastic instability and internal resonance conditions. The objective is to evaluate the influence of stable modes (called passive) usually ignored when discretizing the model. The first step concerns the description of the structural equilibrium path under the action of the mean wind forces. Then, a multiple scale perturbation analysis of the integro-differential equations of motion is performed. Analyzing the stability of the reduced system, the existence of some limit cycles and of successive bifurcations is investigated. The comparison with previous papers, developed in the discrete field, allows clarification of the actual influence of the static equilibrium path and the contribution of passive modes.
Stabilization Control of Hunting Motion of Railway Vehicle Wheelset Using Gyroscopic Damper
Authors: Yabuno Hiroshi , Takano Hirokazu , Okamoto Hirokazu
Published: January 2008

A railway wheelset experiences the problem of hunting motion above a critical speed, which is known as a flutter-type self-excited oscillation owing to a nonconservative contact force. In this study, a stabilization control method is proposed for the hunting motion in a simple wheelset model, i.e. a fundamental two-degrees-of-freedom model with respect to the lateral and yawing motions of the wheelset. Using the theory of linear eigenvalue analysis it is shown that a gyroscopic damper is effective in increasing critical speed for the hunting motion. Experiments were conducted using a simple apparatus with a roller rig, and results show the validity of the gyroscopic damper for the stabilization of hunting motion.
Implementation of Case Management for Batterer Program Participants
Authors: Gondolf Edward W.
Published: January 2008

Among the recommendations for improving batterer counseling is additional services for African American men, which might be obtained through case management that includes individual intake screening, service identification, service contact review, and follow-up calls. A formative evaluation of a case management project was conducted through direct observations of procedures, semistructured interviews with staff, and tabulation of referrals ( N = 202). The men's impressions and recommendations were collected through subsample phone interviews ( n = 72). Most men were referred for job or financial assistance, and few were referred for substance abuse or mental health problems. Barely half of referred men were contacted in the supportive case management phone calls. The average number of referrals per man increased over time, as did referral contacts. Interviews suggest, however, that the referral system had little impact. The case management was not implemented as designed primarily because of time constraints during intake and staff shortcomings. A fuller implementation would cost much more in terms of staffing, supervision, and administration.
Evidence for association of chromosome 10 open reading frame (C10orf27) gene polymorphisms and multiple sclerosis
Authors: Goertsches Robert , Baranzini Sergio E , Morcillo Carlos , Nos Carlos , Camiña Montse , Oksenberg Jorge R , Montalban Xavier , Comabella Manuel
Published: January 2008

A recent association study has provided evidence that chromosome 10q22.1 may contain candidate genes for multiple sclerosis (MS). We analysed two intronic and a non-synonymous single nucleotide polymorphism (SNP) of the C10orf27 gene in 571 patients with MS (relapsing remitting and primary progressive) and healthy controls. Adjusted comparisons revealed significant association with disease susceptibility for one intronic SNP in RRMS individuals and the amino acid modifying SNP for PPMS cases; the latter may also contribute to faster disease progression. Transcript expression in brain lesions from MS patients was increased. These findings suggest C10orf27 as a candidate gene for MS susceptibility and pathogenesis. Multiple selerosis 2008; 14: 412—414. http://msj.sagepub.com
Brain activation patterns elicited by the `Faces Symbol Test' — a pilot fMRI study
Authors: Grabner RH , Popotnig F. , Ropele S. , Neuper C. , Gorani F. , Petrovic K. , Ebner F. , Strasser-Fuchs S. , Fazekas F. , Enzinger C.
Published: January 2008

The Faces Symbol Test (FST) has recently been proposed as a brief and patient-friendly screening instrument for the assessment of cognitive dysfunction in patients with multiple sclerosis (MS). However, in contrast to well-established MS screening tests such as the Paced Auditory Serial Addition Test, the neural correlates of the FST have not been investigated so far. In the present study, we developed a functional MRI (fMRI) version of the FST to provide first data on brain regions and networks involved in this test. A sample of 19 healthy participants completed a version of the FST adapted for fMRI, requiring matching of faces and symbols in a multiple choice test and two further experimental conditions drawing on cognitive subcomponents (face matching and symbol matching). Imaging data showed a differential involvement of a fronto-parieto-occipital network in the three conditions. The most demanding FST condition elicited brain activation patterns related with sustained attention and executive control. These results suggest that the FST recruits brain networks critical for higher-order cognitive functions often impaired in MS patients. Multiple Sclerosis 2008; 14: 354—363. http://msj.sagepub.com
Natural history of secondary-progressive multiple sclerosis
Authors: Tremlett Helen , Yinshan Zhao  , Devonshire Virginia
Published: January 2008

Objective To examine prognosis and risk factors for progression to and from secondary-progressive multiple sclerosis (SPMS).

Methods Patients with definite relapsing—remitting MS (RRMS), onset before July 1988, attending a British—Columbian MS clinic before July 1998, and at least one Expanded Disability Status Scale (EDSS) scores were selected from the population-based database. Time to SPMS (from onset and birth) and the subsequent time to EDSS 8 were examined, as were potential risk factors.

Results In all, 2484/2837 (87.6%) were relapsing—remitting (RR) at onset, with 1445/2484 (58.2%) reaching SPMS, taking a median 18.9 years (95% CI: 18.2—19.7). Those younger at onset took longer to reach SPMS ( P < 0.0005), but did so at a younger age ( P < 0.0005). Males reached SPMS more rapidly from onset and at a younger age ( P < 0.0005), but were around the same age as females at EDSS 8 ( P = 0.975). Characteristics at SPMS onset associated with a longer time from SPMS to EDSS 8 and an older age at EDSS 8 were: longer disease duration ( P < 0.02), older age ( P < 0.01) and lower EDSS ( P < 0.0005). Onset symptoms had little influence on time to SPMS or subsequent progression.

Conclusions The RR phase lasted on average almost two decades, being shorter for males and those older at onset of MS. However, neither were necessarily unfavorable predictors as those older at onset were typically older at SPMS and eventually males and females reached EDSS 8 at around the same age. A longer RR phase was a favorable predictor of disease progression in SPMS. Furthermore, reaching SPMS at an older age or lower EDSS did not necessarily confer a worse outcome. Multiple Sclerosis 2008; 14: 314—324. http://msj.sagepub.com
Progression in familial and nonfamilial MS
Authors: Koch Marcus , Uyttenboogaart Maarten , Heerings Marco , Heersema Dorothea , Mostert Jop , De Keyser Jacques
Published: January 2008

Objective To investigate whether the timing of secondary or primary progression is different between patients with familial and nonfamilial multiple sclerosis (MS).

Methods Information on the family history of 313 patients with MS was taken from our prospective hospital-based database. We used Kaplan—Meier analyses and Cox regression models to evaluate differences between familial and nonfamilial MS in several endpoint measures. We investigated the risk of developing secondary progression in all patients with a relapsing—remitting disease onset, the length of the relapsing—remitting phase and age at onset of progression in patients with secondary progressive MS and the age at disease onset in patients with primary progressive MS (PPMS).

Results Among the primary progressive patients, those with familial MS had a significantly younger age at disease onset than patients with nonfamilial MS (mean 33.04 years versus mean 37.73 years in nonfamilial MS, P = 0.02). There were no significant differences between familial and nonfamilial MS patients in any other investigated measure.

Conclusions Familial MS appears related to the time of disease onset in PPMS. Patients with familial PPMS may be an important patient group for future genetic research in MS. Multiple Sclerosis 2008; 14: 300—306. http://msj.sagepub.com
Multiple sclerosis on-screen: from disaster to coping
Authors: Karenberg Axel
Published: January 2008

Background Fictional portrayals of multiple sclerosis (MS) in film and on television have remained largely unexamined to date. The aim of this review is consequently to catalog and analyse every available film with an MS motif.

Method The author has identified relevant productions by means of international film databases and by handsearch. Each film is systematically evaluated along neurological and cinematic lines.

Results Between 1941 and 2006 MS appeared as a theme in 23 films. Because screenplay writers often make use of medical knowledge, from a neurological perspective many films present a largely accurate picture of this disease's symptoms. The visual character of the medium and the effects of dramatic composition result in the prominence of certain symptoms. Ataxia, paralysis, blurred vision and fatigue are found in films with the same frequency as in epidemiological studies whereas sensory symptoms, eye movement disorders, incontinence and difficulties with sexual function were underrepresented. These films thematize the effects of MS on patients' self-image, the psychological adaptation process and their relations with proxy in a special way. Parallel with improvements in therapy and changing social attitudes toward the handicapped, these films have progressed from the earlier `disaster' to modern `coping' stories.

Conclusion The often life-like portrayal of MS distinguishes these films from the stereotypic representation of other neurological diseases. Because representations of MS in popular media have an immediate effect on an audience of millions, they deserve greater attention from professional neurology. Multiple Sclerosis 2008; 14: 530—540. http://msj.sagepub.com
Long-term (up to 22 years), open-label, compassionate-use study of glatiramer acetate in relapsing—remitting multiple sclerosis
Authors: Miller Aaron , Spada Vincent , Beerkircher Dorothy , Kreitman Rivka Riven
Published: January 2008

To evaluate the safety and efficacy of long-term glatiramer acetate (GA) therapy, 46 patients with relapsing—remitting multiple sclerosis (RRMS) were treated for up to 22 years in an ongoing, open-label study. Kurtzke expanded disability status scale (EDSS) was measured every six months, relapses were reported at occurrence and patients self-reported adverse events (AEs). At GA initiation, disease durations ranged from 0—20 years (median 6.0 years) and at data cut-off (October 2004), GA therapy duration ranged from 1—22 years (median 12.0 years). Mean EDSS score increased 0.9 ± 1.9 from the pretreatment score (3.0 ± 1.8; P = 0.076). Only 10/28 (36%) patients with baseline EDSS <4.0 had a last observed value ≥ 4.0 and 8/34 (24%) with entry EDSS < 6.0 reached EDSS ≥ 6.0. A majority (57%) maintained improved or unchanged EDSS scores. Annualized relapse rate decreased to 0.1 ± 0.2 from 2.9 ± 1.4 prestudy ( P < 0.0001). Of the 18 remaining patients in October 2004 (average disease duration 23 years), 17% with baseline EDSS scores < 4.0 reached EDSS ≥ 4.0 and 28% with baseline scores < 6.0 reached EDSS ≥ 6.0. Adverse events were similar to those reported in short-term clinical trials. This study shows a low rate of relapses and EDSS progression in RRMS patients on GA for up to 22 years. Multiple Sclerosis 2008; 14: 494—499. http://msj.sagepub.com
Making the Most out of 15 Minutes
Authors: Collins Sue
Published: January 2008

Reality TV invites new considerations for theorizing celebrity as a cultural commodity whose economic value is based on potential exchange. In this article, I argue that reality TV's construction of a new stratum of celebrity value—ordinary people performing “the real”—supports claims that the industry is moving toward a “flexible” model of economic organization. The production of reality TV expands the labor stock to include nonunionized, nonpaid or low-paid contestants playing themselves, while also displacing unionized actors from production opportunities. Moreover, reality TV's D-level celebrity generates novelty out of audience self-reflexivity with minimal risk and temporal flexibility. Celebrity value, as a mechanism to gather audiences, undergoes a new form of dispensable synergy that shelters the larger system of celebrity valorization from the dual problems of scarcity and clutter.
KSHV LANA inhibits TGF-β signaling through epigenetic silencing of the TGF-β type II receptor
Authors: Di Bartolo Daniel L. , Cannon Mark , Liu Yi-Fang , Renne Rolf , Chadburn Amy , Boshoff Chris , Cesarman Ethel
Published: January 2008

Signaling through the transforming growth factor–β (TGF-β) pathway results in growth inhibition and induction of apoptosis in various cell types. We show that this pathway is blocked in Kaposi sarcoma herpesvirus (KSHV)–infected primary effusion lymphoma through down-regulation of the TGF-β type II receptor (TβRII) by epigenetic mechanisms. Our data also suggest that KSHV infection may result in lower expression of TβRII in Kaposi sarcoma and multicentric Castleman disease. KSHV-encoded LANA associates with the promoter of TβRII and leads to its methylation and to the deacetylation of proximal histones. Reestablishment of signaling through this pathway reduces viability of these cells, inferring that KSHV-mediated blockage of TGF-β signaling plays a role in the establishment and progression of KSHV-associated neoplasia. These data suggest a mechanism whereby KSHV evades both the antiproliferative effects of TGF-β signaling by silencing TβRII gene expression and immune recognition by suppressing TGF-β–responsive immune cells through the elevated secretion of TGF-β1.
HIF-1α regulates epithelial inflammation by cell autonomous NFκB activation and paracrine stromal remodeling
Authors: Scortegagna Marzia , Cataisson Christophe , Martin Rebecca J. , Hicklin Daniel J. , Schreiber Robert D. , Yuspa Stuart H. , Arbeit Jeffrey M.
Published: January 2008

Hypoxia inducible factor-1 (HIF-1) is a master regulatory transcription factor controlling multiple cell-autonomous and non–cell-autonomous processes, such as metabolism, angiogenesis, matrix invasion, and cancer metastasis. Here we used a new line of transgenic mice with constitutive gain of HIF-1 function in basal keratinocytes and demonstrated a signaling pathway from HIF-1 to nuclear factor κ B (NFκB) activation to enhanced epithelial chemokine and cytokine elaboration. This pathway was responsible for a phenotypically silent accumulation of stromal inflammatory cells and a marked inflammatory hypersensitivity to a single 12-O-tetradecanoylphorbol-13-acetate (TPA) challenge. HIF-1–induced NFκB activation was composed of 2 elements, IκB hyperphosphorylation and phosphorylation of Ser276 on p65, enhancing p65 nuclear localization and transcriptional activity, respectively. NFκB transcriptional targets macrophage inflammatory protein-2 (MIP-2/CXCL2/3), keratinocyte chemokine (KC/CXCL1), and tumor necrosis factor [alfa] (TNFα) were constitutively up-regulated and further increased after TPA challenge both in cultured keratinocytes and in transgenic mice. Whole animal KC, MIP-2, or TNFα immunodepletion each abrogated TPA-induced inflammation, whereas blockade of either VEGF or placenta growth factor (PlGF) signaling did not affect transgenic inflammatory hyper-responsiveness. Thus, epithelial HIF-1 gain of function remodels the local environment by cell-autonomous NFκB-mediated chemokine and cytokine secretion, which may be another mechanism by which HIF-1 facilitates either inflammatory diseases or malignant progression.
The effects of the surface-exposed residues on the binding and hydrolytic activities of Vibrio carchariae chitinase A
Authors: Pantoom Supansa , Songsiriritthigul Chomphunuch , Suginta Wipa
Published: January 2008

Background

Vibrio carchariae chitinase A (EC3.2.1.14) is a family-18 glycosyl hydrolase and comprises three distinct structural domains: i) the amino terminal chitin binding domain (ChBD); ii) the (α/β)8 TIM barrel catalytic domain (CatD); and iii) the α + β insertion domain. The predicted tertiary structure of V. carchariae chitinase A has located the residues Ser33 & Trp70 at the end of ChBD and Trp231 & Tyr245 at the exterior of the catalytic cleft. These residues are surface-exposed and presumably play an important role in chitin hydrolysis.

Results

Point mutations of the target residues of V. carchariae chitinase A were generated by site-directed mutagenesis. With respect to their binding activity towards crystalline α-chitin and colloidal chitin, chitin binding assays demonstrated a considerable decrease for mutants W70A and Y245W, and a notable increase for S33W and W231A. When the specific hydrolyzing activity was determined, mutant W231A displayed reduced hydrolytic activity, whilst Y245W showed enhanced activity. This suggested that an alteration in the hydrolytic activity was not correlated with a change in the ability of the enzyme to bind to chitin polymer. A mutation of Trp70 to Ala caused the most severe loss in both the binding and hydrolytic activities, which suggested that it is essential for crystalline chitin binding and hydrolysis. Mutations varied neither the specific hydrolyzing activity against p NP-[GlcNAc]2, nor the catalytic efficiency against chitohexaose, implying that the mutated residues are not important in oligosaccharide hydrolysis.

Conclusion

Our data provide direct evidence that the binding as well as hydrolytic activities of V. carchariae chitinase A to insoluble chitin are greatly influenced by Trp70 and less influenced by Ser33. Though Trp231 and Tyr245 are involved in chitin hydrolysis, they do not play a major role in the binding process of crystalline chitin and the guidance of the chitin chain into the substrate binding cleft of the enzyme.
Genetic loci linked to Type 1 Diabetes and Multiple Sclerosis families in Sardinia
Authors: Pitzalis Maristella , Zavattari Patrizia , Murru Raffaele , Deidda Elisabetta , Zoledziewska Magdalena , Murru Daniela , Moi Loredana , Motzo Costantino , Orrù Valeria , Costa Gianna , Solla Elisabetta , Fadda Elisabetta , Schirru Lucia , Melis Maria Cristina , Lai Marina , Mancosu Cristina , Tranquilli Stefania , Cuccu Stefania , Rolesu Marcella , Secci Maria Antonietta , Corongiu Daniela , Contu Daniela , Lampis Rosanna , Nucaro Annalisa , Pala Gavino , Pacifico Adolfo , Maioli Mario , Frongia Paola , Chessa Margherita , Ricciardi Rossella , Lostia Stanislao , Marinaro Anna Maria , Milia Anna Franca , Landis Novella , Zedda Maria Antonietta , Whalen Michael B , Santoni Federico , Marrosu Maria Giovanna , Devoto Marcella , Cucca Francesco
Published: January 2008

Background

The Mediterranean island of Sardinia has a strikingly high incidence of the autoimmune disorders Type 1 Diabetes (T1D) and Multiple Sclerosis (MS). Furthermore, the two diseases tend to be co-inherited in the same individuals and in the same families. These observations suggest that some unknown autoimmunity variant with relevant effect size could be fairly common in this founder population and could be detected using linkage analysis.

Methods

To search for T1D and MS loci as well as any that predispose to both diseases, we performed a whole genome linkage scan, sequentially genotyping 593 microsatellite marker loci in 954 individuals distributed in 175 Sardinian families. In total, 413 patients were studied; 285 with T1D, 116 with MS and 12 with both disorders. Model-free linkage analysis was performed on the genotyped samples using the Kong and Cox logarithm of odds (LOD) score statistic.

Results

In T1D, aside from the HLA locus, we found four regions showing a lod-score ≥1; 1p31.1, 6q26, 10q21.2 and 22q11.22. In MS we found three regions showing a lod-score ≥1; 1q42.2, 18p11.21 and 20p12.3. In the combined T1D-MS scan for shared autoimmunity loci, four regions showed a LOD >1, including 6q26, 10q21.2, 20p12.3 and 22q11.22. When we typed more markers in these intervals we obtained suggestive evidence of linkage in the T1D scan at 10q21.2 (LOD = 2.1), in the MS scan at 1q42.2 (LOD = 2.5) and at 18p11.22 (LOD = 2.6). When all T1D and MS families were analysed jointly we obtained suggestive evidence in two regions: at 10q21.1 (LOD score = 2.3) and at 20p12.3 (LOD score = 2.5).

Conclusion

This suggestive evidence of linkage with T1D, MS and both diseases indicates critical chromosome intervals to be followed up in downstream association studies.
Calcitriol affects hCG gene transcription in cultured human syncytiotrophoblasts
Authors: Barrera David , Avila Euclides , Hernández Guillermo , Méndez Isabel , González Leticia , Halhali Ali , Larrea Fernando , Morales Angélica , Díaz Lorenza
Published: January 2008

Background

In pregnancy, maternal serum concentrations of calcitriol significantly rise as a result of increased renal and placental contribution in order to assure calcium supply for the developing fetus. Considering that placenta is a site for vitamin D activation, and the versatility and potency of calcitriol, it is feasible that this hormone participates in fetal/placental development and physiology. In the present work we studied calcitriol actions upon human chorionic gonadotropin (hCG) secretion and expression in cultured trophoblasts, as well as vitamin D receptor (VDR) and CYP27B1 immunolocalization in placental villi.

Methods

Quantification of hCG in culture media was performed by immunoassay. Expression studies were carried out by real time PCR. Analysis of CYP27B1 and VDR localization in placental slides were performed by immunohistochemistry. Statistical significance was established by one way ANOVA using Tukey test for comparisons.

Results

Calcitriol regulated hCG in a time-dependent manner: at 6 h the secosteroid stimulated hCG, whereas longer incubations (24 h) showed opposite effects. Interestingly, calcitriol stimulatory effects on hCG were accompanied by an increase in intracellular cAMP content and were abolished by pre-incubation of the cells with a selective protein kinase A inhibitor. Immunohistochemical techniques showed differential VDR localization in the syncytiotrophoblast layer or in the vascular smooth muscle cells depending on the epitope to which the antibodies were raised (specific for the carboxy- or amino-terminal regions, respectively). CYP27B1 was immunolocalized in the syncytiotrophoblast layer of placental villi.

Conclusion

The presence and location of the vitamin D activating enzyme CYP27B1 as well as the specific receptor for vitamin D were shown in placental sections. The latter, together with findings demonstrating specific effects of calcitriol acting through the VDR and the cAMP/PKA signaling pathway upon hCG expression and secretion, indicate that there is a functional vitamin D endocrine system in the placenta, and recognize calcitriol as an autocrine regulator of hCG.
Hit a New High
Authors: Zhuo Min , Gu Jianguo
Published: January 2008

Over the past three years Molecular Pain has grown steadily and clearly demonstrated its ability to publish novel scientific discoveries in the field of pain research in a timely fashion, hence having a strong and positive impact on pain and neuroscience research. Molecular Pain is now officially tracked by the ISI Web of Science, which allows for the calculation of its impact factor. From this calculation, we have found that Molecular Pain is now ranked at the top among pain journals in the world.
Tobacco industry issues management organizations: Creating a global corporate network to undermine public health
Authors: McDaniel Patricia A , Intinarelli Gina , Malone Ruth E
Published: January 2008

Background

The global tobacco epidemic claims 5 million lives each year, facilitated by the ability of transnational tobacco companies to delay or thwart meaningful tobacco control worldwide. A series of cross-company tobacco industry "issues management organizations" has played an important role in coordinating and implementing common strategies to defeat tobacco control efforts at international, national, and regional levels. This study examines the development and enumerates the activities of these organizations and explores the implications of continuing industry cooperation for global public health.

Methods

Using a snowball sampling strategy, we collected documentary data from tobacco industry documents archives and assembled them into a chronologically organized case study.

Results

The International Committee on Smoking Issues (ICOSI) was formed in 1977 by seven tobacco company chief executives to create common anti-tobacco control strategies and build a global network of regional and national manufacturing associations. The organization's name subsequently changed to INFOTAB. The multinational companies built the organization rapidly: by 1984, it had 69 members operating in 57 countries. INFOTAB material, including position papers and "action kits" helped members challenge local tobacco control measures and maintain tobacco-friendly environments. In 1992 INFOTAB was replaced by two smaller organizations. The Tobacco Documentation Centre, which continues to operate, distributes smoking-related information and industry argumentation to members, some produced by cross-company committees. Agro-Tobacco Services, and now Hallmark Marketing Services, assists the INFOTAB-backed and industry supported International Tobacco Growers Association in advancing claims regarding the economic importance of tobacco in developing nations.

Conclusion

The massive scale and scope of this industry effort illustrate how corporate interests, when threatened by the globalization of public health, sidestep competitive concerns to coordinate their activities. The global network of national and regional manufacturing associations created and nurtured by INFOTAB remains active, particularly in relation to the recently negotiated global health treaty, the Framework Convention on Tobacco Control. Policymakers should be aware that although these associations claim to represent only national or regional interests, they are allied to and coordinated with a confederation of transnational tobacco companies seeking to protect profits by undermining public health.
Derlin-1 is overexpressed in human breast carcinoma and protects cancer cells from endoplasmic reticulum stress-induced apoptosis
Authors: Wang Jiao , Hua Hui , Ran Yuliang , Zhang Hongyin , Liu Weiping , Yang Zhihua , Jiang Yangfu
Published: January 2008

Introduction

Aberrant microenvironment and endoplasmic reticulum (ER) stress are associated with solid-tumor progression. Stress proteins, like heat shock proteins and glucose-regulated proteins, are frequently overexpressed in human tumors. It has been reported that derlin-1 is involved in ER stress response. In vitro studies have demonstrated that derlin-1 participates in the retrotranslocation of misfolded proteins from ER into the cytosol. Because the roles of derlin-1 in human cancer have not yet been characterized, we investigated the expression of derlin-1 in human breast carcinoma and whether it protected cancer cells against ER stress-induced apoptosis.

Methods

Surgical specimens of human breast cancer and/or paired normal tissues from the same patients were collected for immunohistochemical and/or Western blot analysis with anti-human derlin-1 antibody. The expression of derlin-1 in human breast cancer cell lines was detected by reverse transcription-polymerase chain reaction or Western blot. A synthetic small interfering RNA against derlin-1 was introduced into breast cancer cells to inhibit derlin-1 expression. The effects of derlin-1 knockdown on ER stress-induced apoptosis were determined by flow cytometry analysis.

Results

These analyses demonstrated that 66.7% of the breast carcinoma tissues expressed derlin-1, whereas derlin-1 was rarely expressed in normal mammary glands. The expression of derlin-1 in human breast carcinoma correlated with tumor grade and axillary lymph node metastasis. On examining the expression of derlin-1 in human breast cancer cell lines, we found that derlin-1 expression was enhanced by ER stress-inducing agents. Derlin-1 knockdown sensitized breast cancer cells to ER stress-induced apoptosis.

Conclusion

The observed derlin-1 overexpression in breast cancer, together with its function in relieving ER stress-induced apoptosis, suggests that regulation of the ER stress response pathway may be critical in the development and progression of breast cancer.
Biphasic onset of splenic apoptosis following hemorrhagic shock: critical implications for Bax, Bcl-2, and Mcl-1 proteins
Authors: Hostmann Arwed , Jasse Kerstin , Schulze-Tanzil Gundula , Robinson Yohan , Oberholzer Andreas , Ertel Wolfgang , Tschoeke Sven K
Published: January 2008

Introduction

The innate immune response to trauma hemorrhage involves inflammatory mediators, thus promoting cellular dysfunction as well as cell death in diverse tissues. These effects ultimately bear the risk of post-traumatic complications such as organ dysfunction, multiple organ failure, or adult respiratory distress syndrome. In this study, a murine model of resuscitated hemorrhagic shock (HS) was used to determine the apoptosis in spleen as a marker of cellular injury and reduced immune functions.

Methods

Male C57BL-6 mice were subjected to sham operation or resuscitated HS. At t = 0 hours, t = 24 hours, and t = 72 hours, mice were euthanized and the spleens were removed and evaluated for apoptotic changes via DNA fragmentation, caspase activities, and activation of both extrinsic and intrinsic apoptotic pathways. Spleens from untreated mice were used as control samples.

Results

HS was associated with distinct lymphocytopenia as early as t = 0 hours after hemorrhage without regaining baseline levels within the consecutive 72 hours when compared with sham and control groups. A rapid activation of splenic apoptosis in HS mice was observed at t = 0 hours and t = 72 hours after hemorrhage and predominantly confirmed by increased DNA fragmentation, elevated caspase-3/7, caspase-8, and caspase-9 activities, and enhanced expression of intrinsic mitochondrial proteins. Accordingly, mitochondrial pro-apoptotic Bax and anti-apoptotic Bcl-2 proteins were inversely expressed within the 72-hour observation period, thereby supporting significant pro-apoptotic changes. Solely at t = 24 hours, expression of the anti-apoptotic Mcl-1 protein shows a significant increase when compared with sham-operated and control animals. Furthermore, expression of extrinsic death receptors were only slightly increased.

Conclusion

Our data suggest that HS induces apoptotic changes in spleen through a biphasic caspase-dependent mechanism and imply a detrimental imbalance of pro- and anti-apoptotic mitochondrial proteins Bax, Bcl-2, and Mcl-1, thereby promoting post-traumatic immunosuppression.
Exploring systemic RNA interference in insects: a genome-wide survey for RNAi genes in Tribolium
Authors: Tomoyasu Yoshinori , Miller Sherry C , Tomita Shuichiro , Schoppmeier Michael , Grossmann Daniela , Bucher Gregor
Published: January 2008

Background

RNA interference (RNAi) is a highly conserved cellular mechanism. In some organisms, such as Caenorhabditis elegans, the RNAi response can be transmitted systemically. Some insects also exhibit a systemic RNAi response. However, Drosophila, the leading insect model organism, does not show a robust systemic RNAi response, necessitating another model system to study the molecular mechanism of systemic RNAi in insects.

Results

We used Tribolium, which exhibits robust systemic RNAi, as an alternative model system. We have identified the core RNAi genes, as well as genes potentially involved in systemic RNAi, from the Tribolium genome. Both phylogenetic and functional analyses suggest that Tribolium has a somewhat larger inventory of core component genes than Drosophila, perhaps allowing a more sensitive response to double-stranded RNA (dsRNA). We also identified three Tribolium homologs of C. elegans sid-1, which encodes a possible dsRNA channel. However, detailed sequence analysis has revealed that these Tribolium homologs share more identity with another C. elegans gene, tag-130. We analyzed tag-130 mutants, and found that this gene does not have a function in systemic RNAi in C. elegans. Likewise, the Tribolium sid-like genes do not seem to be required for systemic RNAi. These results suggest that insect sid-1-like genes have a different function than dsRNA uptake. Moreover, Tribolium lacks homologs of several genes important for RNAi in C. elegans.

Conclusion

Although both Tribolium and C. elegans show a robust systemic RNAi response, our genome-wide survey reveals significant differences between the RNAi mechanisms of these organisms. Thus, insects may use an alternative mechanism for the systemic RNAi response. Understanding this process would assist with rendering other insects amenable to systemic RNAi, and may influence pest control approaches.
KRAS Mutations As an Independent Prognostic Factor in Patients With Advanced Colorectal Cancer Treated With Cetuximab
Authors: Lièvre Astrid , Bachet Jean-Baptiste , Boige Valérie , Cayre Anne , Le Corre Delphine , Buc Emmanuel , Ychou Marc , Bouché Olivier , Landi Bruno , Louvet Christophe , André Thierry , Bibeau Fréderic , Diebold Marie-Danièle , Rougier Philippe , Ducreux Michel , Tomasic Gorana , Emile Jean-François , Penault-Llorca Frédérique , Laurent-Puig Pierre
Published: January 2008

Purpose

Cetuximab is efficient in advanced colorectal cancer (CRC). We previously showed that KRAS mutations were associated with resistance to cetuximab in 30 CRC patients. The aim of this study was to validate, in an independent larger series of 89 patients, the prognostic value of KRAS mutations on response to cetuximab and survival.

Patients and Methods

Eighty-nine metastatic CRC patients treated with cetuximab after treatment failure with irinotecan-based chemotherapy were analyzed for KRAS mutation by allelic discrimination on tumor DNA. The association between KRAS mutations and tumor response, skin toxicity, progression-free survival (PFS) and overall survival (OS) was analyzed.

Results

A KRAS mutation was present in 27% of the patients and was associated with resistance to cetuximab (0% v 40% of responders among the 24 mutated and 65 nonmutated patients, respectively; P < .001) and a poorer survival (median PFS: 10.1 v 31.4 weeks in patients without mutation; P = .0001; median OS: 10.1 v 14.3 months in patients without mutation; P = .026). When we pooled these 89 patients with patients from our previous study, the multivariate analysis showed that KRAS status was an independent prognostic factor associated with OS and PFS, whereas skin toxicity was only associated with OS. In a combined analysis, median OS times of patients with two, one, or no favorable prognostic factors (severe skin toxicity and no KRAS mutation) was of 15.6, 10.7, and 5.6 months, respectively.

Conclusion

These results confirm the high prognostic value of KRAS mutations on response to cetuximab and survival in metastatic CRC patients treated with cetuximab.
Randomized, Phase III Study of Weekly Paclitaxel in Combination With Carboplatin Versus Standard Every-3-Weeks Administration of Carboplatin and Paclitaxel for Patients With Previously Untreated Advanced Non–Small-Cell Lung Cancer
Authors: Belani Chandra P. , Ramalingam Suresh , Perry Michael C. , LaRocca Renato V. , Rinaldi David , Gable Preston S. , Tester William J.
Published: January 2008

Purpose

To compare the efficacy and safety of weekly paclitaxel in combination with carboplatin administered every 4 weeks to the standard regimen of paclitaxel and carboplatin administered every 3 weeks for the treatment of patients with advanced non–small-cell lung cancer (NSCLC).

Patients and Methods

Four hundred forty-four patients with previously untreated stage IIIB/IV NSCLC were randomly assigned to either arm 1 (n = 223), paclitaxel 100 mg/m2 weekly for 3 of 4 weeks with carboplatin area under the curve (AUC) = 6 mg/mL · min on day 1 of each 4 week cycle, or arm 2 (n = 221), paclitaxel 225 mg/m2 and carboplatin AUC = 6 on day 1 of each 3-week cycle. After four cycles of therapy, patients in both treatment arms were eligible to continue weekly paclitaxel (70 mg/m2, 3 of 4 weeks) as maintenance therapy until unacceptable toxicity or disease progression.

Results

The objective response rate was 27.6% for arm 1 and 19.2% for arm 2. Median time to progression (TTP) was 18.4 and median survival (MS) was 38.6 weeks for arm 1. For arm 2, the median TTP and MS were 16.7 weeks and 42.9 weeks respectively. Grade 3/4 anemia was more common with arm 1, although grade 2/3 neuropathy and arthralgia were less common. The remainder of the toxicities were similar between the two arms.

Conclusion

All efficacy parameters were similar between the two treatment arms. The favorable nonhematologic toxicity profile of arm 1 makes this an alternative treatment option for patients with advanced NSCLC.
cT3N0 Rectal Cancer: Potential Overtreatment With Preoperative Chemoradiotherapy Is Warranted
Authors: Guillem José G. , Díaz-González Juan A. , Minsky Bruce D. , Valentini Vincenzo , Jeong Seung-Yong , Rodriguez-Bigas Miguel A. , Coco Claudio , Leon Rebecca , Hernandez-Lizoain José L. , Aristu José J. , Riedel Elyn R. , Nitti Donato , Wong W. Douglas , Pucciarelli Salvatore
Published: January 2008

Purpose

Although combined-modality therapy (CMT) is the preferred treatment for T3 and/or lymph node (LN)-positive rectal cancer, the German rectal cancer study published in 2004 demonstrated that 18% of patients deemed suitable for preoperative CMT by endorectal ultrasound (ERUS) may be overstaged. Because data also suggest that LN-negative rectal cancer after total mesorectal excision may not require radiotherapy, it is reasonable to consider omitting radiotherapy for the cT3N0 subset. We therefore determined the accuracy of pre-CMT ERUS or magnetic resonance imaging (MRI) staging, to explore the validity of a nonpreoperative CMT approach for cT3N0 disease.

Patients and Methods

One hundred eighty-eight ERUS-/MRI-staged T3N0 rectal cancer patients received preoperative CMT (fluorouracil based and 45-50.4 Gy) followed by radical resection. Rates of pathologic complete response (pCR) and mesorectal LN involvement were determined.

Results

Tumors were located a median of 5 cm from the anal verge. Sphincter-preserving surgery was performed in 143 patients (76%). Overall pCR was 20%, and 41 patients (22%) had pathologically positive mesorectal LNs. The incidence of positive LNs significantly increased with T stage: ypT0, 3%; ypT1, 7%; ypT2, 20%; ypT3-4, 36% (P = .001).

Conclusion

The accuracy of preoperative ERUS/MRI for staging mid to distal cT3N0 rectal cancer is limited because 22% of patients have undetected mesorectal LN involvement despite CMT. Therefore, ERUS-/MRI-staged T3N0 rectal cancer patients should continue to receive preoperative CMT. Although 18% may be overstaged and therefore overtreated, our data suggest that an even larger number would be understaged and require postoperative CMT, which is associated with significantly inferior local control, higher toxicity, and worse functional outcome.
Randomized Trial Comparing Bleomycin/Etoposide/Cisplatin With Alternating Cisplatin/Cyclophosphamide/Doxorubicin and Vinblastine/Bleomycin Regimens of Chemotherapy for Patients With Intermediate- and Poor-Risk Metastatic Nonseminomatous Germ Cell Tumors: Genito-Urinary Group of the French Federation of Cancer Centers Trial T93MP
Authors: Culine Stéphane , Kramar Andrew , Théodore Christine , Geoffrois Lionel , Chevreau Christine , Biron Pierre , Nguyen Binh Bui , Héron Jean-François , Kerbrat Pierre , Caty Armelle , Delva Rémy , Fargeot Pierre , Fizazi Karim , Bouzy Jeannine , Droz Jean-Pierre
Published: January 2008

Purpose

Two chemotherapy regimens for intermediate- and poor-risk metastatic nonseminomatous germ cell tumors were compared for efficacy and toxicity.

Patients and Methods

From February 1994 to February 2000, 190 patients were randomly assigned between either four cycles of BEP (bleomycin 30 mg d1, d8, d15; etoposide 100 mg/m2 d1-5; cisplatin 20 mg/m2 d1-5) or four to six alternating cycles of CISCA/VB (cyclophosphamide 400 mg/m2 d1-2, doxorubicin 35 mg/m2 d1-2, cisplatin 100 mg/m2 d3/vinblastine 2.5 mg/m2 d1-5, bleomycin 25 mg/m2 d1-5). Risk was initially defined according to the Institut Gustave Roussy (Villejuif, France) prognostic model based on serum alpha-fetoprotein and human chorionic gonadotropin levels only. Patients were retrospectively assigned into the International Germ Cell Consensus Classification.

Results

Among 185 assessable patients, favorable responses did not differ statistically between the two arms: 49 in the CISCA/VB arm (56%; 95% CI, 45% to 66%), 57 in the BEP arm (65%; 95% CI, 55% to 75%). The CISCA/VB regimen induced more significant hematologic and mucous toxicities compared with the BEP arm. The 5-year event-free survival rates were 37% (95% CI, 27% to 47%) and 47% (95% CI, 37% to 57%) in CISCA/VB and BEP arms, respectively (hazard ratio [HR] = 0.76; 95% CI, 0.52 to 1.11; P = .15). With a median follow-up of 7.8 years, the 5-year overall survival rates were 59% (95% CI, 47% to 67%) and 69% (95% CI, 58% to 77%) in CISCA/VB and BEP arms, respectively (HR = 0.73; 95% CI, 0.46 to 1.18; P = .24).

Conclusion

Because of equivalent efficacy and lesser toxicity, the standard treatment for patients with intermediate- and poor-risk metastatic nonseminomatous germ cell tumors remains four cycles of BEP.
Human Immunodeficiency Virus–Associated Squamous Cell Cancer of the Anus: Epidemiology and Outcomes in the Highly Active Antiretroviral Therapy Era
Authors: Chiao Elizabeth Y. , Giordano Thomas P. , Richardson Peter , El-Serag Hashem B.
Published: January 2008

Purpose

To evaluate and determine predictors of squamous cell carcinoma of the anus (SCCA) outcomes in the highly active antiretroviral therapy (HAART) era for HIV-positive and -negative individuals using large national Veterans Affairs (VA) Administration databases.

Patients and Methods

We used the VA administrative databases to perform a retrospective cohort study in 1,184 veterans diagnosed with SCCA between 1998 and 2004. We calculated HIV infection rates and used logistic regression to identify epidemiologic factors that were associated with HIV infection. Kaplan-Meier curves and Cox proportional hazards models were calculated to compare survival between HIV-positive and HIV-negative veterans.

Results

In our cohort, 175 patients (15%) were HIV positive. The median age of the HIV-negative and -positive patients was 63 and 49 years, respectively (P < .001). Individuals with HIV were eight times more likely to be male (P = .01) and three times more likely to be African American (P < .001). There were no differences between HIV-positive and HIV-negative individuals in the receipt of treatment. The 2-year observed survival rates were 77% and 75% among HIV-positive and HIV-negative individuals, respectively. In multivariate Cox analysis, significant predictors of survival were age, sex, metastasis at diagnosis, and comorbidity score. HIV infection did not affect survival.

Conclusion

A noteworthy proportion of individuals with SCCA in the VA system are HIV positive. HIV-associated SCCA seems mainly to be a disease among younger men. Survival of SCCA is equivalent between HIV-positive and HIV-negative individuals in the HAART era. Treatment should not be withheld or deintensified based on HIV status.
6-STEPPPs: A Modular Tool to Facilitate Clinician Participation in Fair Decisions for Funding New Cancer Drugs
Authors: Browman George P. , Manns Braden , Hagen Neil , Chambers Carole R. , Simon Anita , Sinclair Shane
Published: January 2008

Purpose:

To design a tool to assist clinician participation with cancer drug funding decisions. Public policy-makers and insurers are struggling with funding decisions regarding increasingly expensive new cancer drugs. Increasingly, oncologists are contributing to the process of review that leads to such decisions. We were asked to design a system for ranking new cancer drugs for priority-based funding decisions.

Methods:

The “Accountability for Reasonableness” framework informed the design of a six-module multistakeholder decision process blending evidence-based traditional technology assessment methods with individual and cultural values elicitation. The tool was piloted in three settings: (1) videotaped simulated multistakeholder deliberation sessions; (2) clinical oncology leaders; and (3) a regional (Canadian provincial) pharmacy and therapeutics committee making formulary decisions. The modules involve: decision clarification, drug eligibility screening (filtering), clinical performance scoring index, cost modeling, data integration and values clarification, and process evaluation.

Results:

The tool was feasible to use, acceptable to participants, and able to rank candidate drugs. The pharmacy and therapeutics committee with whom it was tested used the tool as a part of their deliberations, and the tumor group leaders requested its incorporation into organization-based decision making.

Conclusion:

The decision tool can facilitate priority-based cancer drug funding decisions that meet the conditions of fairness as perceived by participants, including oncologists.
Antioxidant and antibacterial activity of two compounds (forsythiaside and forsythin) isolated from Forsythia suspensa
Authors: Qu Huanhuan , Zhang Yongmin , Wang Yan , Li Baixue , Sun Wenji
Published: January 2008

Forsythia suspensa (Thunb.) Vahl. has been widely used in traditional medicines in Asia to treat gonorrhoea, erysipelas, inflammation, pyrexia, ulcer and other diseases. Recently the investigation has been focused on the antioxidant and antibacterial activity of this plant. However, limited scientifically proven information is available. We isolated two compounds (forsythiaside and forsythin) from this plant. The aims of this investigation, therefore, were to assay antioxidant activity and antibacterial properties of the two main and distinctive compounds isolated and to exploit antioxidants and antibacterial agents from natural compounds. The antioxidant activity was estimated using the 1-diphenyl-2-picrylhydrazyl (DPPH) scavenging activity method and the in-vitro antimicrobial activity was evaluated by microtitre plate method. Forsythiaside was found to possess strong antioxidant and antibacterial activity but forsythin was much weaker. Owing to these properties, the study can be further extended to exploit the possible application of forsythiaside as an alternative antioxidant and antibacterial agent of natural origin.