bluuebunny/crossref_metadata_2025 huggingface dataset:
Predicting gene ontology functions from protein's regional surface structures
Authors: Liu Zhi-Ping , Wu Ling-Yun , Wang Yong , Chen Luonan , Zhang Xiang-Sun
Published: December 2007

Background

Annotation of protein functions is an important task in the post-genomic era. Most early approaches for this task exploit only the sequence or global structure information. However, protein surfaces are believed to be crucial to protein functions because they are the main interfaces to facilitate biological interactions. Recently, several databases related to structural surfaces, such as pockets and cavities, have been constructed with a comprehensive library of identified surface structures. For example, CASTp provides identification and measurements of surface accessible pockets as well as interior inaccessible cavities.

Results

A novel method was proposed to predict the Gene Ontology (GO) functions of proteins from the pocket similarity network, which is constructed according to the structure similarities of pockets. The statistics of the networks were presented to explore the relationship between the similar pockets and GO functions of proteins. Cross-validation experiments were conducted to evaluate the performance of the proposed method. Results and codes are available at: http://zhangroup.aporc.org/bioinfo/PSN/.

Conclusion

The computational results demonstrate that the proposed method based on the pocket similarity network is effective and efficient for predicting GO functions of proteins in terms of both computational complexity and prediction accuracy. The proposed method revealed strong relationship between small surface patterns (or pockets) and GO functions, which can be further used to identify active sites or functional motifs. The high quality performance of the prediction method together with the statistics also indicates that pockets play essential roles in biological interactions or the GO functions. Moreover, in addition to pockets, the proposed network framework can also be used for adopting other protein spatial surface patterns to predict the protein functions.
CD209 in inflammatory bowel disease: a case-control study in the Spanish population
Authors: Núñez Concepción , Oliver Javier , Mendoza Juan Luis , Gómez-García María , Taxonera Carlos , Gómez Luis M , López-Nevot Miguel A , de la Concha Emilio G , Urcelay Elena , Martínez Alfonso , Martín Javier
Published: December 2007

Background

The etiology of Ulcerative Colitis (UC) and Crohn's Disease (CD), considered together as Inflammatory Bowel Diseases (IBD), involves environmental and genetic factors. Although some genes are already known, the genetics underlying these diseases is complex and new candidates are continuously emerging. The CD209 gene is located in a region linked previously to IBD and a CD209 functional polymorphism (rs4804803) has been associated to other inflammatory conditions. Our aim was to study the potential involvement of this CD209 variant in IBD susceptibility.

Methods

We performed a case-control study with 515 CD patients, 497 UC patients and 731 healthy controls, all of them white Spaniards. Samples were typed for the CD209 single nucleotide polymorphism (SNP) rs4804803 by TaqMan technology. Frequency comparisons were performed using χ2 tests.

Results

No association between CD209 and UC or CD was observed initially. However, stratification of UC patients by HLA-DR3 status, a strong protective allele, showed that carriage of the CD209_G allele could increase susceptibility in the subgroup of HLA-DR3-positive individuals (p = 0.03 OR = 1.77 95% CI 1.04–3.02, vs. controls).

Conclusion

A functional variant in the CD209 gene, rs4804803, does not seem to be influencing Crohn's disease susceptibility. However, it could be involved in the etiology or pathology of Ulcerative Colitis in HLA-DR3-positive individuals but further studies are necessary.
Sensitization of catastrophic cognition in cognitive-behavioral therapy for panic disorder
Authors: Noda Yumiko , Nakano Yumi , Lee Kiyoe , Ogawa Sei , Kinoshita Yoshihiro , Funayama Tadashi , Watanabe Norio , Chen Junwen , Noguchi Yuka , Kataoka Miyako , Suzuki Masako , Furukawa Toshi A
Published: December 2007

Background

Cognitive model of panic disorder have proposed that panic attacks result from the catastrophic misinterpretation of certain bodily sensations. Cognitive-Behavioral Therapy (CBT) for panic disorder aims to change these catastrophic cognitions. CBT intervention successfully caused reduction of catastrophic cognitions and symptomatic improvement in the majority of cases. However there are some patients who fail to modify their catastrophic cognitions or rather experience an increase in them during CBT treatment. It is clinically and theoretically important to understand about cognitive sensitization of panic disorder during CBT sessions. The purpose of the present study is 1) to clarify the baseline characteristics of panic patients who would experience sensitization of their catastrophic cognitions through the CBT treatment, and 2) to examine the course of symptomatic changes for them.

Methods

Of ninety-five outpatients with panic disorder started the group CBT program for treatment of panic disorder, seventy-nine completer were classified as "cognitively sensitized (CS)" or "cognitive responding (CR)" or "no-responder" according to the difference of the Agoraphobic Cognitions Questionnaire score across treatment. We compared the CS and CR patients in terms of their baseline clinical characteristics. Then we assessed the symptomatic and functional changes for both groups.

Results

At the start of the CBT program, despite of the same degree of panic disorder severity, CS scored significantly lower on ACQ score than CR. CS also showed significantly lower score on anticipatory anxiety compared to CR. At the end of treatment CS showed significant improvement in severity of panic disorder, although the degree of improvement was smaller than that for CR. Then CS would progressively reduce their agoraphobic fear and avoidance, and would improve their functional impairment up to three month of follow-up.

Conclusion

Panic patients who would experience sensitization of their catastrophic cognitions through the CBT treatment could nonetheless gradually improve. They showed a relatively low level of catastrophic cognition and anticipatory anxiety before starting the CBT program. We might conclude that temporary sensitization of catastrophic cognition may be necessary before improvement especially among those with initially low catastrophic body sensation fears and that we need not be concerned too much with temporary increase in catastrophic cognition in the process of CBT for panic disorder.
Validation of a method for identifying nursing home admissions using administrative claims
Authors: Zuckerman Ilene H , Sato Masayo , Hsu Van Doren , Hernandez Jose J
Published: December 2007

Background

Currently there is no standard algorithm to identify whether a subject is residing in a nursing home from administrative claims. Our objective was to develop and validate an algorithm that identifies nursing home admissions at the resident-month level using the MarketScan Medicare Supplemental and Coordination of Benefit (COB) database.

Methods

The computer algorithms for identifying nursing home admissions were created by using provider type, place of service, and procedure codes from the 2000 – 2002 MarketScan Medicare COB database. After the algorithms were reviewed and refined, they were compared with a detailed claims review by an expert reviewer. A random sample of 150 subjects from the claims was selected and used for the validity analysis of the algorithms. Contingency table analysis, comparison of mean differences, correlations, and t-test analyses were performed. Percentage agreement, sensitivity, specificity, and Kappa statistics were analyzed.

Results

The computer algorithm showed strong agreement with the expert review (99.9%) for identification of the first month of nursing home residence, with high sensitivity (96.7%), specificity (100%) and a Kappa statistic of 0.97. Weighted Pearson correlation coefficient between the algorithm and the expert review was 0.97 (p < 0.0001).

Conclusion

A reliable algorithm indicating evidence of nursing home admission was developed and validated from administrative claims data. Our algorithm can be a useful tool to identify patient transitions from and to nursing homes, as well as to screen and monitor for factors associated with nursing home admission and nursing home discharge.
Reconstruction and flux analysis of coupling between metabolic pathways of astrocytes and neurons: application to cerebral hypoxia
Authors: Çakιr Tunahan , Alsan Selma , Saybaşιlι Hale , Akιn Ata , Ülgen Kutlu Ö
Published: December 2007

Background

It is a daunting task to identify all the metabolic pathways of brain energy metabolism and develop a dynamic simulation environment that will cover a time scale ranging from seconds to hours. To simplify this task and make it more practicable, we undertook stoichiometric modeling of brain energy metabolism with the major aim of including the main interacting pathways in and between astrocytes and neurons.

Model

The constructed model includes central metabolism (glycolysis, pentose phosphate pathway, TCA cycle), lipid metabolism, reactive oxygen species (ROS) detoxification, amino acid metabolism (synthesis and catabolism), the well-known glutamate-glutamine cycle, other coupling reactions between astrocytes and neurons, and neurotransmitter metabolism. This is, to our knowledge, the most comprehensive attempt at stoichiometric modeling of brain metabolism to date in terms of its coverage of a wide range of metabolic pathways. We then attempted to model the basal physiological behaviour and hypoxic behaviour of the brain cells where astrocytes and neurons are tightly coupled.

Results

The reconstructed stoichiometric reaction model included 217 reactions (184 internal, 33 exchange) and 216 metabolites (183 internal, 33 external) distributed in and between astrocytes and neurons. Flux balance analysis (FBA) techniques were applied to the reconstructed model to elucidate the underlying cellular principles of neuron-astrocyte coupling. Simulation of resting conditions under the constraints of maximization of glutamate/glutamine/GABA cycle fluxes between the two cell types with subsequent minimization of Euclidean norm of fluxes resulted in a flux distribution in accordance with literature-based findings. As a further validation of our model, the effect of oxygen deprivation (hypoxia) on fluxes was simulated using an FBA-derivative approach, known as minimization of metabolic adjustment (MOMA). The results show the power of the constructed model to simulate disease behaviour on the flux level, and its potential to analyze cellular metabolic behaviourin silico.

Conclusion

The predictive power of the constructed model for the key flux distributions, especially central carbon metabolism and glutamate-glutamine cycle fluxes, and its application to hypoxia is promising. The resultant acceptable predictions strengthen the power of such stoichiometric models in the analysis of mammalian cell metabolism.
Muscle fatigue in relation to forearm pain and tenderness among professional computer users
Authors: Thomsen Gert F , Johnson Pete W , Svendsen Susanne W , Kryger Ann I , Bonde Jens Peter E
Published: December 2007

Background

To examine the hypothesis that forearm pain with palpation tenderness in computer users is associated with increased extensor muscle fatigue.

Methods

Eighteen persons with pain and moderate to severe palpation tenderness in the extensor muscle group of the right forearm and twenty gender and age matched referents without such complaints were enrolled from the Danish NUDATA study of neck and upper extremity disorders among technical assistants and machine technicians. Fatigue of the right forearm extensor muscles was assessed by muscle twitch forces in response to low frequency (2 Hz) percutaneous electrical stimulation. Twitch forces were measured before, immediately after and 15 minutes into recovery of an extensor isometric wrist extension for ten minutes at 15 % Maximal Voluntary Contraction (MVC).

Results

The average MVC wrist extension force and baseline stimulated twitch forces were equal in the case and the referent group. After the fatiguing contraction, a decrease in muscle average twitch force was seen in both groups, but the decrease was largest in the referent group: 27% (95% CI 17–37) versus 9% (95% CI -2 to 20). This difference in twitch force response was not explained by differences in the MVC or body mass index.

Conclusion

Computer users with forearm pain and moderate to severe palpation tenderness had diminished forearm extensor muscle fatigue response. Additional studies are necessary to determine whether this result reflects an adaptive response to exposure without any pathophysiological significance, or represents a part of a causal pathway leading to pain.
Evidence against roles for phorbol binding protein Munc13-1, ADAM adaptor Eve-1, or vesicle trafficking phosphoproteins Munc18 or NSF as phospho-state-sensitive modulators of phorbol/PKC-activated Alzheimer APP ectodomain shedding
Authors: Ikin Annat F , Causevic Mirsada , Pedrini Steve , Benson Lyndsey S , Buxbaum Joseph D , Suzuki Toshiharu , Lovestone Simon , Higashiyama Shigeki , Mustelin Tomas , Burgoyne Robert D , Gandy Sam
Published: December 2007

Background

Shedding of the Alzheimer amyloid precursor protein (APP) ectodomain can be accelerated by phorbol esters, compounds that act via protein kinase C (PKC) or through unconventional phorbol-binding proteins such as Munc13-1. We have previously demonstrated that application of phorbol esters or purified PKC potentiates budding of APP-bearing secretory vesicles at the trans-Golgi network (TGN) and toward the plasma membrane where APP becomes a substrate for enzymes responsible for shedding, known collectively as α-secretase(s). However, molecular identification of the presumptive "phospho-state-sensitive modulators of ectodomain shedding" (PMES) responsible for regulated shedding has been challenging. Here, we examined the effects on APP ectodomain shedding of four phorbol-sensitive proteins involved in regulation of vesicular membrane trafficking of APP: Munc13-1, Munc18, NSF, and Eve-1.

Results

Overexpression of either phorbol-sensitive wildtype Munc13-1 or phorbol-insensitive Munc13-1 H567K resulted in increased basal APP ectodomain shedding. However, in contrast to the report of Roßner et al (2004), phorbol ester-dependent APP ectodomain shedding from cells overexpressing APP and Munc13-1 wildtype was indistinguishable from that observed following application of phorbol to cells overexpressing APP and Munc13-1 H567K mutant. This pattern of similar effects on basal and stimulated APP shedding was also observed for Munc18 and NSF. Eve-1, an ADAM adaptor protein reported to be essential for PKC-regulated shedding of pro-EGF, was found to play no obvious role in regulated shedding of sAPPα.

Conclusion

Our results indicate that, in the HEK293 system, Munc13-1, Munc18, NSF, and EVE-1 fail to meet essential criteria for identity as PMES for APP.
Delays in childhood immunization in a conflict area: a study from Sierra Leone during civil war
Authors: Senessie Charles , Gage George N , von Elm Erik
Published: December 2007

Background

Sierra Leone has undergone a decade of civil war from 1991 to 2001. From this period few data on immunization coverage are available, and conflict-related delays in immunization according to the Expanded Programme on Immunization (EPI) schedule have not been investigated. We aimed to study delays in childhood immunization in the context of civil war in a Sierra Leonean community.

Methods

We conducted an immunization survey in Kissy Mess-Mess in the Greater Freetown area in 1998/99 using a two-stage sampling method. Based on immunization cards and verbal history we collected data on immunization for tuberculosis, diphtheria, tetanus, pertussis, polio, and measles by age group (0–8/9–11/12–23/24–35 months). We studied differences between age groups and explored temporal associations with war-related hostilities taking place in the community.

Results

We included 286 children who received 1690 vaccine doses; card retention was 87%. In 243 children (85%, 95% confidence interval (CI): 80–89%) immunization was up-to-date. In 161 of these children (56%, 95%CI: 50–62%) full age-appropriate immunization was achieved; in 82 (29%, 95%CI: 24–34%) immunization was not appropriate for age. In the remaining 43 children immunization was partial in 37 (13%, 95%CI: 9–17) and absent in 6 (2%, 95%CI: 1–5). Immunization status varied across age groups. In children aged 9–11 months the proportion with age-inappropriate (delayed) immunization was higher than in other age groups suggesting an association with war-related hostilities in the community.

Conclusion

Only about half of children under three years received full age-appropriate immunization. In children born during a period of increased hostilities, immunization was mostly inappropriate for age, but recommended immunizations were not completely abandoned. Missing or delayed immunization represents an additional threat to the health of children living in conflict areas.
Methionine aminopeptidase-2 blockade reduces chronic collagen-induced arthritis: potential role for angiogenesis inhibition
Authors: Bainbridge John , Madden Leigh , Essex David , Binks Michael , Malhotra Rajneesh , Paleolog Ewa M
Published: December 2007

The enzyme methionine aminopeptidase-2 (MetAP-2) is thought to play an important function in human endothelial cell proliferation, and as such provides a valuable target in both inflammation and cancer. Rheumatoid arthritis (RA) is a chronic inflammatory disease associated with increased synovial vascularity, and hence is a potential therapeutic target for angiogenesis inhibitors. We examined the use of PPI-2458, a selective non-reversible inhibitor of MetAP-2, in disease models of RA, namely acute and chronic collagen-induced arthritis (CIA) in mice. Whilst acute CIA is a monophasic disease, CIA induced with murine collagen type II manifests as a chronic relapsing arthritis and mimics more closely the disease course of RA. Our study showed PPI-2458 was able to reduce clinical signs of arthritis in both acute and chronic CIA models. This reduction in arthritis was paralleled by decreased joint inflammation and destruction. Detailed mechanism of action studies demonstrated that PPI-2458 inhibited human endothelial cell proliferation and angiogenesis in vitro, without affecting production of inflammatory cytokines. Furthermore, we also investigated release of inflammatory cytokines and chemokines from human RA synovial cell cultures, and observed no effect of PPI-2458 on spontaneous expression of cytokines and chemokines, or indeed on the angiogenic molecule vascular endothelial growth factor (VEGF). These results highlight MetAP-2 as a good candidate for therapeutic intervention in RA.
Plasma neutrophil gelatinase-associated lipocalin predicts acute kidney injury, morbidity and mortality after pediatric cardiac surgery: a prospective uncontrolled cohort study
Authors: Dent Catherine L , Ma Qing , Dastrala Sudha , Bennett Michael , Mitsnefes Mark M , Barasch Jonathan , Devarajan Prasad
Published: December 2007

Introduction

Acute kidney injury (AKI) is a frequent complication of cardiopulmonary bypass (CPB). The lack of early biomarkers has impaired our ability to intervene in a timely manner. We previously showed in a small cohort of patients that plasma neutrophil gelatinase-associated lipocalin (NGAL), measured using a research enzyme-linked immunosorbent assay, is an early predictive biomarker of AKI after CPB. In this study we tested whether a point-of-care NGAL device can predict AKI after CPB in a larger cohort.

Methods

First, in a cross-sectional pilot study including 40 plasma samples (NGAL range 60 to 730 ng/ml) and 12 calibration standards (NGAL range 0 to 1,925 ng/ml), NGAL measurements by enzyme-linked immunosorbent assay and by Triage® NGAL Device (Biosite Inc., San Diego, CA, USA) were highly correlated (r = 0.94). Second, in a subsequent prospective uncontrolled cohort study, 120 children undergoing CPB were enrolled. Plasma was collected at baseline and at frequent intervals for 24 hours after CPB, and analyzed for NGAL using the Triage® NGAL device. The primary outcome was AKI, which was defined as a 50% or greater increase in serum creatinine.

Results

AKI developed in 45 patients (37%), but the diagnosis using serum creatinine was delayed by 2 to 3 days after CPB. In contrast, mean plasma NGAL levels increased threefold within 2 hours of CPB and remained significantly elevated for the duration of the study. By multivariate analysis, plasma NGAL at 2 hours after CPB was the most powerful independent predictor of AKI (β = 0.004, P < 0.0001). For the 2-hour plasma NGAL measurement, the area under the curve was 0.96, sensitivity was 0.84, and specificity was 0.94 for prediction of AKI using a cut-off value of 150 ng/ml. The 2 hour postoperative plasma NGAL levels strongly correlated with change in creatinine (r = 0.46, P < 0.001), duration of AKI (r = 0.57, P < 0.001), and length of hospital stay (r = 0.44, P < 0.001). The 12-hour plasma NGAL strongly correlated with mortality (r = 0.48, P = 0.004) and all measures of morbidity mentioned above.

Conclusion

Accurate measurements of plasma NGAL are obtained using the point-of-care Triage® NGAL device. Plasma NGAL is an early predictive biomarker of AKI, morbidity, and mortality after pediatric CPB.
Transcriptional profiling of MnSOD-mediated lifespan extension in Drosophilareveals a species-general network of aging and metabolic genes
Authors: Curtis Christina , Landis Gary N , Folk Donna , Wehr Nancy B , Hoe Nicholas , Waskar Morris , Abdueva Diana , Skvortsov Dmitriy , Ford Daniel , Luu Allan , Badrinath Ananth , Levine Rodney L , Bradley Timothy J , Tavaré Simon , Tower John
Published: December 2007

Background

Several interventions increase lifespan in model organisms, including reduced insulin/insulin-like growth factor-like signaling (IIS), FOXO transcription factor activation, dietary restriction, and superoxide dismutase (SOD) over-expression. One question is whether these manipulations function through different mechanisms, or whether they intersect on common processes affecting aging.

Results

A doxycycline-regulated system was used to over-express manganese-SOD (MnSOD) in adult Drosophila, yielding increases in mean and maximal lifespan of 20%. Increased lifespan resulted from lowered initial mortality rate and required MnSOD over-expression in the adult. Transcriptional profiling indicated that the expression of specific genes was altered by MnSOD in a manner opposite to their pattern during normal aging, revealing a set of candidate biomarkers of aging enriched for carbohydrate metabolism and electron transport genes and suggesting a true delay in physiological aging, rather than a novel phenotype. Strikingly, cross-dataset comparisons indicated that the pattern of gene expression caused by MnSOD was similar to that observed in long-lived Caenorhabditis elegans insulin-like signaling mutants and to the xenobiotic stress response, thus exposing potential conserved longevity promoting genes and implicating detoxification in Drosophila longevity.

Conclusion

The data suggest that MnSOD up-regulation and a retrograde signal of reactive oxygen species from the mitochondria normally function as an intermediate step in the extension of lifespan caused by reduced insulin-like signaling in various species. The results implicate a species-conserved net of coordinated genes that affect the rate of senescence by modulating energetic efficiency, purine biosynthesis, apoptotic pathways, endocrine signals, and the detoxification and excretion of metabolites.
A case for immunization against nosocomial infections
Authors: Cross Alan S , Chen Wilbur H , Levine Myron M
Published: December 2007

Immunization is a highly effective public health measure that reduces the incidence of infectious diseases, yet there has been relatively little effort toward the development of vaccines for nosocomial infections. Many nosocomial infections originate on mucosal surfaces (e.g., respiratory or gastrointestinal mucosa). As patients who are hospitalized once are more likely to be hospitalized again, we propose a prime-boost immunization strategy, whereby a priming dose of vaccine for a nosocomial infection is administered mucosally. Upon readmission, a parenteral boost would elicit a rapid immune response locally and systemically. Such a strategy could reduce or ameliorate nosocomial infections and perhaps limit dissemination of nosocomial pathogens. Thus, a more aggressive effort to develop vaccines for nosocomial infections is warranted.
NF-κB-dependent control of HIV-1 transcription by the second coding exon of Tat in T cells
Authors: Mahlknecht Ulrich , Dichamp Isabelle , Varin Audrey , Van Lint Carine , Herbein Georges
Published: December 2007

HIV-1 two-exon transactivator protein (Tat) is a 101-aa protein. We investigated the possible contribution of the extreme C terminus of HIV-1 Tat to maximize nuclear transcription factor NF-κB activation, long terminal repeat (LTR) transactivation, and viral replication in T cells. C-terminal deletion and substitution mutants made with the infectious clone HIV-89.6 were assayed for their ability to transactivate NF-κB-secreted alkaline phosphatase and HIV-1 LTR-luciferase reporter constructs for low concentrations of Tat. A mutant infectious clone of HIV-89.6 engineered by introducing a stop codon at aa 72 in the Tat open-reading frame (HIVΔtatexon2) replicated at a significantly lower rate than the wild-type HIV-89.6 in phytohemagglutinin-A/IL-2-stimulated primary peripheral blood lymphocytes. Altogether, our results suggest a critical role for the glutamic acids at positions 92, 94, and 96 or lysines at positions 88, 89, and 90, present in the second encoding Tat exon in activating NF-κB, transactivating the HIV-1 LTR and enhancing HIV-1 replication in T cells.
TRAF6 distinctively mediates MyD88- and IRAK-1-induced activation of NF-κB
Authors: Muroi Masashi , Tanamoto Ken-ichi
Published: December 2007

MyD88 and IL-1R-associated kinase 1 (IRAK-1) play crucial roles as adaptor molecules in signal transduction of the TLR/IL-1R superfamily, and it is known that expression of these proteins leads to the activation of NF-κB in a TNFR-associated factor 6 (TRAF6)-dependent manner. We found in this study, however, that a dominant-negative mutant of TRAF6, lacking the N-terminal RING and zinc-finger domain, did not inhibit IRAK-1-induced activation of NF-κB in human embryonic kidney 293 cells, although the TRAF6 mutant strongly suppressed the MyD88-induced activation. The dominant-negative mutant of TRAF6 did not affect the IRAK-1-induced activation, regardless of the expression level of IRAK-1. In contrast, small interfering RNA silencing of TRAF6 expression inhibited MyD88-induced and IRAK-1-induced activation, and supplementation with the TRAF6 dominant-negative mutant did not restore the IRAK-1-induced activation. Expression of IRAK-1, but not MyD88, induced the oligomerization of TRAF6, and IRAK-1 and the TRAF6 dominant-negative mutant were associated with TRAF6. These results indicate that TRAF6 is involved but with different mechanisms in MyD88-induced and IRAK-induced activation of NF-κB and suggest that TRAF6 uses a distinctive mechanism to activate NF-κB depending on signals.
Predictors of Tamoxifen Discontinuation Among Older Women With Estrogen Receptor–Positive Breast Cancer
Authors: Owusu Cynthia , Buist Diana S.M. , Field Terry S. , Lash Timothy L. , Thwin Soe Soe , Geiger Ann M. , Quinn Virginia P. , Frost Floyd , Prout Marianne , Yood Marianne Ulcickas , Wei Feifei , Silliman Rebecca A.
Published: December 2007

Purpose

Five years of adjuvant tamoxifen therapy for estrogen receptor (ER) –positive breast cancer is more effective than 2 years of use. However, information on tamoxifen discontinuation is scanty. We sought to identify predictors of tamoxifen discontinuation among older women with breast cancer.

Patients and Methods

Within six health care delivery systems, we identified women ≥ 65 years old diagnosed with stage I to IIB ER-positive or indeterminant breast cancer between 1990 and 1994 who had filled a prescription for adjuvant tamoxifen. We observed them for 5 years after initial tamoxifen prescription. We used automated pharmacy records to validate tamoxifen prescription information abstracted from medical records. The primary end point was tamoxifen discontinuation, operationalized as ever discontinuing tamoxifen during 5 years of follow-up. We used Cox proportional hazards to identify predictors of tamoxifen discontinuation.

Results

Of 961 women who were prescribed tamoxifen, 49% discontinued tamoxifen before the completion of 5 years. Discontinuers were more likely to be aged 75 to less than 80 years (v < 70 years; hazard ratio [HR] = 1.41; 95% CI, 1.06 to 1.87), be aged ≥ 80 years (HR = 2.02; 95% CI, 1.53 to 2.66), have an increase in Charlson Comorbidity Index at 3 years from diagnosis (HR = 1.52; 95% CI, 1.18 to 1.95), have an increase in the number of cardiopulmonary comorbidities at 3 years (HR = 1.75; 95% CI, 1.34 to 2.28), have indeterminant ER status (v ER-positive status; HR = 1.36; 95% CI, 1.00 to 1.85), and have received breast-conserving surgery (BCS) without radiotherapy (v mastectomy; HR = 1.62; 95% CI, 1.18 to 2.22).

Conclusion

Attention to nonadherence among older women at risk of discontinuation, particularly those receiving BCS without radiotherapy, might improve breast cancer outcomes for these women.
High-Dose Therapy and Autologous Stem-Cell Transplantation in Angioimmunoblastic Lymphoma: Complete Remission at Transplantation Is the Major Determinant of Outcome—Lymphoma Working Party of the European Group for Blood and Marrow Transplantation
Authors: Kyriakou Charalampia , Canals Carmen , Goldstone Anthony , Caballero Dolores , Metzner Bernd , Kobbe Guido , Kolb Hans-Jochem , Kienast Joachim , Reimer Peter , Finke Jurgen , Oberg Gunnar , Hunter Ann , Theorin Niklas , Sureda Anna , Schmitz Norbert
Published: December 2007

Purpose

Patients with angioimmunoblastic T-cell lymphoma (AITL) have poor prognoses with current conventional chemotherapy. The aim of this study was to evaluate the effect of high-dose therapy (HDT) followed by autologous stem-cell transplantation (ASCT) on patients with AITL.

Patients and Methods

We report a retrospective, multicenter study of 146 patients with AITL who received ASCT. The source of the stem cells was peripheral blood in 143 patients. The conditioning regimen varied, and 74% of the patients received carmustine and 1,3-bis(2-chloroethyl)-1-nitrosourea; etoposide; ara-C; and melphalan chemotherapy.

Results

After a median follow-up of 31 months (range, 3 to 174 months), 95 patients (65%) remained alive, and 51 patients (35%) died. Forty-two patients died as a result of disease progression, and nine died as a result of regimen-related toxicity. The cumulative incidence of nonrelapse mortality was 5% and 7% at 12 and 24 months, respectively. The actuarial overall survival (OS) was 67% at 24 months and 59% at 48 months. The cumulative incidence of relapse was estimated at 40% and 51% at 24 and 48 months, respectively. Disease status at transplantation was the major factor that impacted outcome. Patients who received a transplant during first complete remission (CR) had significantly superior progression-free survival and OS. The estimated PFS rates for patients who received their transplants in CR were 70% and 56% at 24 and 48 months, respectively; 42% and 30% for patients with chemotherapy-sensitive disease at those time points, respectively; and 23% at both time points for patients with chemotherapy-refractory disease.

Conclusion

This study shows that HDT and ASCT offers the possibility of long-term disease-free survival to patients with AITL. Early transplantation is necessary to achieve optimal results.
Genetic and Environmental Influence on Structural Strength of Weight-Bearing and Non–Weight-Bearing Bone: A Twin Study
Authors: Mikkola Tuija M , Sipilä Sarianna , Rantanen Taina , Sievänen Harri , Suominen Harri , Kaprio Jaakko , Koskenvuo Markku , Kauppinen Markku , Heinonen Ari
Published: December 2007

A bivariate genetic analysis among 217 older female twin pairs showed that, although the structural strength of tibia and radius are mainly regulated by same genetic and environmental factors, the tibia is more affected by environment.

Introduction: The habitual loading environment of the bone may modulate the relative contribution of genetic and environmental factors to bone structure. The purpose of this study was to estimate the contribution of the common and site-specific genetic and environmental factors to interindividual variation in compressive structural strength of the weight-bearing tibia and non–weight-bearing radius.

Materials and Methods: pQCT scans were obtained from both members of 103 monozygotic (MZ) and 114 dizygotic (DZ) 63- to 76-yr-old female twin pairs to estimate the compressive strength of the distal tibia and distal radius. Quantitative genetic models were used to decompose the phenotypic variance into additive genetic, shared environmental, and individual environmental effects at each bone site and to study whether these bone sites share genetic or environmental effects.

Results: The MZ and DZ twins did not differ in mean age, height, weight, or bone structural strength. The age-adjusted Cholesky model showed that additive genetic factors accounted for 83% (95% CI, 77–88%) of the variance in radial strength and 61% (95% CI, 52–69%) of the variance in tibial strength, and these were fully correlated. A shared environmental factor accounted for 15% (95% CI, 10–20%) of tibial strength. An individual environmental factor accounted for 17% (95% CI, 12–23%) of the variance in radial strength and 10% (95% CI, 5–17%) of the variance in tibial strength. The relative contribution of an individual environmental factor specific to tibial strength was 14% (95% CI, 11–18%).

Conclusions: The results suggest that, in older women, the majority of the individual differences in the compressive structural strength of the forearm and leg are regulated by genetic and environmental factors that are common to both bone sites. However, the relative importance of environmental factors was greater for the weight-bearing tibia than for the non–weight-bearing radius. Thus, the heritability of bone strength seems to vary between skeletal sites according to differences in the typical loading environment.
Long-Term Protective Effects of Zoledronic Acid on Cancellous and Cortical Bone in the Ovariectomized Rat
Authors: Gasser Jürg A , Ingold Peter , Venturiere Andrea , Shen Victor , Green Jonathan R
Published: December 2007

Current bisphosphonate therapies effectively prevent bone loss in postmenopausal women. We studied the effect of a single intravenous dose of ZOL in ovariectomized rats. Protection from bone loss was dose dependent, lasting for up to 32 weeks, supporting the rationale for an annual intravenous dosing regimen of ZOL for treatment of postmenopausal osteoporosis.

Introduction: Once-yearly dosing with zoledronic acid (ZOL) 5 mg can increase BMD and reduce fracture rate in postmenopausal women with low BMD. The primary objective of this study was to determine the duration of bone protective effects of a single dose of ZOL in ovariectomized rats, an animal model of postmenopausal osteopenia. Secondary objectives were to determine the effects on bone turnover and mechanical properties.

Materials and Methods: Female Wistar rats (10 per group) received single intravenous doses of ZOL 0.8, 4, 20, 100, or 500 μg/kg, alendronate 200 μg/kg, or isotonic saline 4 days before bilateral ovariectomy. Sham-operated controls were pretreated with saline. Mass and density of cancellous and cortical bone (pQCT) were measured at 4-wk intervals for 32 wk. Bone architecture (μCT), bone formation dynamics (fluorochrome label-based histomorphometry), and biomechanical strength in compression testing were also assessed at 32 wk.

Results: Ovariectomy-associated BMD loss was significantly attenuated for 32 wk by ZOL ≥4 μg/kg for total BMD, ZOL ≥20 μg/kg for cortical BMD, and ZOL ≥4 μg/kg for cancellous BMD (p < 0.01 versus ovariectomized controls). Alendronate 200 μg/kg was of equivalent potency to ZOL 20 μg/kg. Ovariectomy-associated decreases in trabecular architectural parameters were dose-dependently attenuated by ZOL. Alendronate 200 μg/kg was equivalent to ZOL 20 μg/kg. The bone resorption marker TRACP5b indicated transient suppression of elevated osteoclast activity by ZOL relative to OVX-rats even at the lowest dose of 0.8 μg/kg, whereas at 100–500 μg/kg, the effect was significant relative to the OVX control for the entire duration of the study of 32 wk. Bone formation parameters were not significantly affected by ZOL 20 μg/kg but were significantly reduced by ZOL 100–500 μg/kg. Alendronate 200 μg/kg was equivalent to ZOL 100 μg/kg. ZOL produced dose-related improvements in bone strength parameters after ovariectomy. Alendronate 200 μg/kg was of similar potency to ZOL 20 μg/kg.

Conclusions: The duration and magnitude of the bone-protecting effect of a single intravenous dose of ZOL in ovariectomized rats is dose dependent and lasts for up to 32 wk. Compared with alendronate, ZOL shows 10-fold higher potency in preventing bone loss. These data support the use of an annual intravenous ZOL dosing regimen for the treatment of osteoporosis.
An Immunohistochemical Method for Identifying Fibroblasts in Formalin-fixed, Paraffin-embedded Tissue
Authors: Goodpaster Tracy , Legesse-Miller Aster , Hameed Meera R. , Aisner Seena C. , Randolph-Habecker Julie , Coller Hilary A.
Published: December 2007

Fibroblasts are critical for tissue homeostasis, and their inappropriate proliferation and activation can result in common and debilitating conditions including fibrosis and cancer. We currently have a poor understanding of the mechanisms that control the growth and activation of fibroblasts in vivo, in part because of a lack of suitable fibroblast markers. We have taken advantage of an antibody previously shown to stain stromal cells in frozen tissues (TE-7) and identified conditions in which it can be used to stain fibroblasts and myofibroblasts in the paraffin-embedded tissue samples routinely collected for pathological analysis. We show that this antibody recognizes growing and quiescent fibroblasts and myofibroblasts by immunohistochemistry, immunofluorescence, and ELISA assays. We also present its staining patterns in normal tissue samples and in breast tumors.
Raman Nanoparticle Probes for Antibody-based Protein Detection in Tissues
Authors: Lutz Barry , Dentinger Claire , Sun Lei , Nguyen Lienchi , Zhang Jingwu , Chmura AJ , Allen April , Chan Selena , Knudsen Beatrice
Published: December 2007

Surface-enhanced Raman scattering (SERS) nanoparticles are emerging as a new approach for optical detection of biomolecules. In a model assay in formalin-fixed paraffin-embedded (FFPE) prostate tissue sections, we detect prostate-specific antigen (PSA) using antibody (Ab) conjugated to composite organic–inorganic nanoparticles (COINs), and we use identical staining protocols to compare COIN-Ab and Alexa–Ab conjugates in adjacent tissue sections. Spectral analysis illustrates the fundamental difference between fluorescence and Raman signatures and accurately extracts COIN probe signals from background autofluorescence. Probe signals are used to generate images of PSA expression on the tissue, and quality measures are presented to characterize the performance of the COIN assay in comparison to Alexa. Staining accuracy (ability to correctly identify PSA expression in epithelial cells) is somewhat less for COIN than Alexa, which is attributed to an elevated false negative rate of the COIN. However, COIN provided signal intensities comparable to Alexa, and good intra-, inter-, and lot-to-lot consistencies. Overall, COIN and Alexa detection reagents possess similar performance with FFPE tissues, supporting the further development of Raman probes for this application. This manuscript contains online supplemental material at http://www.jhc.org . Please visit this article online to view these materials.
Time Courses of Growth and Remodeling of Porcine Aortic Media During Hypertension: A Quantitative Immunohistochemical Examination
Authors: Hu Jin-Jia , Ambrus Andy , Fossum Theresa W. , Miller Matthew W. , Humphrey Jay D. , Wilson Emily
Published: December 2007

Arteries undergo marked structural and functional changes in human and experimental hypertension that generally involve smooth muscle cell (SMC) hypertrophy/hyperplasia as well as abnormal extracellular matrix turnover. In this study we examined time courses of changes in SMC activity and matrix protein content in a novel mini-pig aortic coarctation model. Cell proliferation was evaluated by immunostaining of Ki-67, apoptosis was assessed by TUNEL, and phenotypic changes were monitored by immunostaining three SMC contractile markers (caldesmon, calponin, and smoothelin). Changes in medial collagen and elastin were examined by picrosirius red and Verhoeff–van Gieson staining, respectively. LabVIEW-based image analysis routines were developed to objectively and efficiently quantify the (immuno)histochemical results. We found that significant cell proliferation and matrix production occurred in the early stages of this coarctation model and then declined gradually; the SMCs also tended to exhibit a less contractile phenotype following these cellular and extracellular changes. Specifically, different aspects of the phenotypic changes associated with hypertension occurred at different rates: cell proliferation and collagen production occurred early and peaked by 2 weeks, whereas changes in contractile protein expression continued to decrease over the entire 8-week study period. Temporal changes found in this study emphasize the importance of simultaneously tracing time courses of SMC growth and differentiation as well as matrix protein production and content. SMCs are multifunctional, and caution must be used to not overdefine phenotype. This manuscript contains online supplemental material at http://www.jhc.org . Please visit this article online to view these materials.
Nitrosylcobalamin Potentiates the Anti-Neoplastic Effects of Chemotherapeutic Agents via Suppression of Survival Signaling
Authors: Bauer Joseph A. , Lupica Joseph A. , Szugye Heidi , Morrison Bei H. , Haney Rebecca M. , Masci Rhonda K. , Lee Rebecca M. , DiDonato Joseph A. , Lindner Daniel J.
Published: December 2007

Background

Nitrosylcobalamin (NO-Cbl) is a chemotherapeutic pro-drug derived from vitamin B12 that preferentially delivers nitric oxide (NO) to tumor cells, based upon increased receptor expression. NO-Cbl induces Apo2L/TRAIL-mediated apoptosis and inhibits survival signaling in a variety of malignant cell lines. Chemotherapeutic agents often simultaneously induce an apoptotic signal and activation of NF-κB, which has the undesired effect of promoting cell survival. The specific aims of this study were to 1) measure the anti-tumor effects of NO-Cbl alone and in combination with conventional chemotherapeutic agents, and to 2) examine the mechanism of action of NO-Cbl as a single agent and in combination therapy.

Methodology

Using anti-proliferative assays, electrophoretic mobility shift assay (EMSA), immunoblot analysis and kinase assays, we demonstrate an increase in the effectiveness of chemotherapeutic agents in combination with NO-Cbl as a result of suppressed NF-κB activation.

Results

Eighteen chemotherapeutic agents were tested in combination with NO-Cbl, in thirteen malignant cell lines, resulting in a synergistic anti-proliferative effect in 78% of the combinations tested. NO-Cbl pre-treatment resulted in decreased NF-κB DNA binding activity, inhibition of IκB kinase (IKK) enzymatic activity, decreased AKT activation, increased caspase-8 and PARP cleavage, and decreased cellular XIAP protein levels.

Conclusion

The use of NO-Cbl to inhibit survival signaling may enhance drug efficacy by preventing concomitant activation of NF-κB or AKT.
Norbert Bachleitner / Franz M. Eybl / Ernst Fischer, Geschichte des Buchhandels in Österreich. 2000
Authors: Niedermeier Stephan
Published: December 2007

Als bisher umfangreichster Band der von Herbert G. Göpfert, Alberto Martino und Reinhard Wittmann herausgegebenen Reihe Geschichte des Buchhandels, einer Sammlung nationaler Buchhandelsgeschichten, ist im Jahre 2000 die Geschichte des Buchhandels in Österreich erschienen. Die ersten vier Kapitel bis zum Jahre 1790 (S. 1–157) hat Franz M. Eybl geschrieben, die beiden Kapitel für die Zeit von 1790 bis 1918 (S. 158–240) stammen von Norbert Bachleitner und die abschließenden drei Kapitel von Ernst Fischer (S. 241–368). Autoren und Kapitel werden einander nur durch einen Satz im Vorwort zugeordnet. Sowohl in der Gliederung der Kapitel als auch in ihren Grundannahmen folgen die drei Autoren einheitlichen Prinzipien. Das Buch macht daher einen sehr geschlossenen Eindruck.
Dietrich Krusche, Zeigen im Text. Anschauliche Orientierung in literarischen Modellen von Welt. 2001
Authors: Rall Marlene
Published: December 2007

Vielleicht bedarf es eines kleinen Hinweises, damit der Titel des Buches so einleuchtend wird, wie er sich spätestens nach der Lektüre des zweiten Kapitels erweist. Für die mit der deutschsprachigen Philologie vertrauten Leser ist der Bezug auf Karl Bühler sofort ersichtlich. Der Wiener Psycholinguist hat in seinem Standardwerk Sprachtheorie von 1934 den Sprechakt in der natürlichen Kommunikation untersucht. Wie vor ihm bereits der schwedische Forscher Adolf Noreen unterscheidet Bühler zwei Funktionen der Sprache, die er als Felder bezeichnet: das Zeigfeld mit den Zeigwörtern und das Symbolfeld mit den Nennwörtern. Der größte Teil der Wörter einer Sprache hat symbolische Funktion, indem sie die Welt der Gegenstände und Sachverhalte nennen, wodurch diese anschaulich werden. Die Zeigwörter dagegen sind ohne einen konkreten Sprechanlaß nicht verständlich.
Susanne Wehde, Typographische Kultur. Eine zeichentheoretische und kulturgeschichtliche Studie zur Typographie und ihrer Entwicklung. 2000
Authors: Hebekus Uwe
Published: December 2007

Mit den Studien Michael Gieseckes ist offenbar geworden, daß eine kulturwissenschaftliche Konzentration auf die ‚Materialität des Signifikanten‘ nicht in jedem Fall eine ‚Subversion des Sinns‘ zutage fördert. Wie sehr beispielsweise Kommunikation, die sich gedruckter Lettern bedient, schon aufgrund ihrer Form und der technischen Apparatur, die sie ermöglicht, wie sehr mithin typographische Kultur in ihrer konkreten Gestalt auch Ort der Instituierung eines sozialen und politischen Imaginären – etwa der Nation – ist, hat Giesecke gezeigt. Auf dem Problemfeld der angeführten Studien bewegt sich auch die umfang- und sehr materialreiche Arbeit Susanne Wehdes.