bluuebunny/crossref_metadata_2025 huggingface dataset:
Nonirradiated versus Irradiated Achilles Allograft
Authors: Rappe Matthew , Horodyski MaryBeth , Meister Keith , Indelicato Peter A.
Published: May 2007

Background

Many studies suggest that gamma irradiation decreases allograft strength in a dose-dependent manner. No study has demonstrated that this decrease in strength translates into higher clinical failures.

Hypothesis

Irradiation of allograft tissue will lead to higher early clinical failure in anterior cruciate ligament (ACL) reconstruction.

Study Design

Cohort study; Level of evidence, 3.

Methods

Medical records were reviewed for 90 consecutive patients who had received Achilles allograft reconstruction for unilateral primary ACL injuries at one institution between July 2001 and June 2002. One half of patients received nonirradiated Achilles allograft and the other half received irradiated Achilles allograft at a dose range of 2.0 to 2.5 Mrad. The ACL allograft reconstructions were performed using the same surgical technique. The rehabilitation program was identical for both groups. All clinical failures were recorded.

Results

At least 6 months’ follow-up was available on 42 subjects in the nonirradiated group and 33 subjects in the irradiated group. A significant difference was noted in early failure rates between the groups (P < .01). The nonirradiated group had 1 in 42 (2.4%) catastrophic failure. In the irradiated group, 11 of 33 (33%) Achilles tendon grafts failed.

Conclusions

Less than satisfactory results led the senior authors to discontinue the use of irradiated allografts in ACL surgery. Continued research into alternatives to gamma irradiation is needed.
The Motivational Properties of Tangible Incentives
Authors: Jeffrey Scott A. , Shaffer Victoria
Published: May 2007

Employers who spend considerable sums on noncash tangible incentives need to document their effectiveness and investigate the best means of delivery.
New Forms of Organization Don't Justify Skill-Based Pay
Authors: Giancola Frank
Published: May 2007

Current trends in organizational design do not necessarily require a shift in how jobs are evaluated and employees are paid.
Reward Management: On the Line
Authors: Brown Duncan , Purcell John
Published: May 2007

Successful organizations involve line managers in plan design and implementation and provide them with full support.
Branch Office Salary Structures
Authors: Atchison Thomas J.
Published: May 2007

Companies expanding into new markets may need to establish separate branch office salary structures to maintain internal equity and external competitiveness.
What Are Key Pay Issues Right Now?
Authors: Zingheim Patricia K. , Schuster Jay R.
Published: May 2007

Employers can adopt basic guidelines to determine whether performance should be measured collectively or individually and to ensure that performance pay programs are worth the effort.
Bloodroot: Life Stories of Nurse Practitioners in Rural Appalachia
Authors: Caldwell Debbie Rife
Published: May 2007

This nursing research study was designed to reveal the life stories of nurse practitioners in rural Appalachia using storytelling and ballad elements of the culture. The researcher was born in a rural Appalachian community in Virginia and was summoned to return to the place of her birth, feeling an invisible kinship to land, blood ties to family, and a longing to honor rural nursing. Seven nurse practitioners from the same community shared their life stories. Using the heuristic phenomenological research method of Moustakas, the researcher became storyteller. The metaphor of bloodroot emerged as the unity of meaning for the life stories. The theme essences were revealed as interconnection: intricate patterns of rural Appalachian culture, intertwining relationships, interrelationships, and inner journey. “Brand New Home,” an Appalachian bluegrass ballad, along with pictures of Appalachia, underpins and culminates this study as a creative synthesis. Implications for nursing practice, education, and research are included.
Perceptions of Health Among Immigrant Latino Adolescents From Mexico
Authors: Garcia Carolyn M. , Duckett Laura J. , Saewyc Elizabeth M. , Bearinger Linda H.
Published: May 2007

Purpose: This ethnographic study describes the health-related perceptions of immigrant Latino adolescents from Mexico. Method: Fourteen adolescents, purposively recruited from two non-health-based community settings, participated. Each was interviewed twice and completed a visual narrative project using disposable cameras. Audiotaped transcripts and photographs were inductively analyzed. Findings: Being healthy is holistically perceived by these adolescents and includes physical, mental, spiritual, social, and environmental factors. Pictures portrayed healthy and unhealthy influences and behaviors, including eating habits, exercise, self-care, relationships, garbage, and pollution. Personal responsibility was important in being healthy and in promoting one's health. Family was identified as an important source of health-related information. Implications: Nurses recognizing the holistic, comprehensive health-related perceptions of immigrant Latino adolescents can promote their health and design culturally and developmentally appropriate educational strategies and health interventions aimed at eliminating health disparities.
Nursing Home Residents' Sense of Coherence and Functional Status Decline
Authors: Cole Catherine S.
Published: May 2007

Functional status decline places an enormous burden on health care services and strategies to identify at risk subgroups are needed. The purpose of this study was to examine the relationship between sense of coherence (SOC) and functional status to determine if SOC can be used to identify at-risk subgroups. In a convenience sample ( N = 65) of nursing home residents measures of functional status and SOC were compared at 2 times. The mean functional status score of the weak SOC group ( n = 28) at Time 1 was 16.14 and 17.32 at Time 2 indicating functional status decline. The mean functional status score of the strong SOC group ( n = 37) at Time 1 was 12.38 and 11.76 at Time 2 indicating improved functional status. Although these changes were not statistically significant the trends suggest that a weak SOC may indicate increased risk for functional status decline.
Exploring Improvisation in Nursing
Authors: Hanley Mary Anne , Fenton Mary V.
Published: May 2007

Improvisation has long been considered a function of music, dance, and the theatre arts. An exploration of the definitions and characteristics of this concept in relation to the art and practice of nursing provide an opportunity to illuminate related qualities within the field of nursing. Nursing has always demonstrated improvisation because it is often required to meet the needs of patients in a rapidly changing environment. However, little has been done to identify improvisation in the practice of nursing or to teach improvisation as a nursing knowledge-based skill. This article strives to explore the concept of improvisation in nursing, to describe the characteristics of improvisation as applied to nursing, and to utilize case studies to illustrate various manifestations of improvisation in nursing practice.
Effects of Holistic Nursing Course
Authors: Downey Marty
Published: May 2007

A study of an undergraduate course in holistic nursing was conducted to determine its impact on personal and professional health care practices. A mixed method design was used to examine responses on a sample of 200 participants. Results indicated a positive personal impact with continued application of concepts into professional health practices. Personal and professional nursing practices were influenced from 1 to 7 years after completing the holistic nursing course. After introduction of the concepts of self-care and holistic approaches to health, students and graduates experienced a shift in values and beliefs related to their own health practices. Continued exposure to holistic practices creates a pattern of awareness toward health that affects future personal and professional nursing practice, creating a paradigm shift for emerging nursing students and graduates from the course. This affects the manner in which nurses meet the needs of their clients in a variety of settings.
Beginning Your Vita Contemplativa
Authors: Bartunek Jean M.
Published: May 2007

In this article, I describe some of the topics intellectual autobiographies might include, summarize some of what I and others have said in intellectual autobiographies published in Organization Studies , and invite readers to begin the process of constructing their own. To this end, I suggest some questions and a process readers might use.
Scholarship and Teaching That Matters: Juxtaposing Inner Freedom With Street-Smart Credibility
Authors: Delbecq André L.
Published: May 2007

This article describes a step-process approach to scholarship that links a scholar's personal interests with societal needs. It allows professional insight (knowledge from experience) to be juxtaposed with theoretical insight (knowledge from science). It also facilitates a publication flow protective of academic career advancement.
The Third Road
Authors: Fukami Cynthia V.
Published: May 2007

Most business schools expect faculty members to be good researchers or good teachers, but not both. Groomed to be successful at a research institution, there was little emphasis placed on the author's development as a teacher. In her first full-time job, she found that there were few rewards for effective teaching. Based on her own experiences in the classroom and support from colleagues in the Organizational Behavior Teaching Society, the author successfully searched for a career that combined teaching and research. The essay concludes with advice to doctoral students and others who aspire to pursue the scholarship of teaching and learning.
Writing From Teaching: A Textbook Writer's Tale
Authors: Hatch Mary Jo
Published: May 2007

A textbook author tells of her early struggle to become a textbook writer, the long journey and the many detours she took along the way to getting her first textbook published. Having identified early in her career that writing a textbook was her chosen way to have an impact on her field of organization theory, she encountered many obstacles to realizing her ambition. She ultimately found a way to use her teaching to facilitate getting her book published. To those others who also aspire to author texts as part of their scholarly endeavor, she offers her lessons learned with the hope that they do not have to follow the roundabout route that she took.
F. J. Roethlisberger and the Elusive Phenomena of Organizational Behavior
Authors: Vaill Peter B.
Published: May 2007

In 1961, Fritz Roethlisberger, coauthor of the landmark Hawthorne studies, wrote a memorandum sketching his understanding of the nascent field of organizational behavior. The memo's purpose was to discuss the relationships of theory and practice in the field, identifying in particular some of the tensions and contradictions that the field poses for the relations of theory and practice. This article reprints Roethlisberger's memo in its entirety and comments point for point on the contemporary relevance of his assertions about the relations of theory and practice. Roethlisberger's observations are even more relevant today than they were in 1961, given the growth of academic theory and research in organizational behavior and the explosion in organizations of ever more complex and intractable problems of managerial leadership. The article will be of interest to anyone interested in the relations of theory and practice and particularly to younger scholars who are shaping their research programs and teaching philosophies.
Principles of Effective Course Design: What I Wish I Had Known About Learning-Centered Teaching 30 Years Ago
Authors: Whetten David A.
Published: May 2007

Ten years ago, after 20 years as a university professor, I was asked to direct the teaching and learning support center at my university. I quickly realized I had almost no knowledge of the published scholarship on this subject. From my reading of this literature, I found the research on the predictors of student learning particularly informative. In particular, I gained an appreciation for the impact of course design. In this article, I summarize a framework for designing “significant learning experiences.” In discussing the three key components of course design (learning outcomes, learning activities, and learning assessments), I offer tips and give examples relevant for the field of management. My intent is to share the most important information I have learned from a decade of conversations with experts on student learning—the things I wish someone had taught me 30 years ago.
Your Teaching Portfolio: Strategies for Initiating and Documenting Growth and Development
Authors: Ouellett Mathew L.
Published: May 2007

An introduction to the concept of the teaching portfolio, this article provides several short- and long-term strategies related to documenting teaching-development efforts. In particular, it provides a persuasive rationale for why one should consider dedicating precious time and resources documenting teaching goals and development and how the activity itself can make one a better instructor.
Mutations in the cofilin partner Aip1/Wdr1 cause autoinflammatory disease and macrothrombocytopenia
Authors: Kile Benjamin T. , Panopoulos Athanasia D. , Stirzaker Roslynn A. , Hacking Douglas F. , Tahtamouni Lubna H. , Willson Tracy A. , Mielke Lisa A. , Henley Katya J. , Zhang Jian-Guo , Wicks Ian P. , Stevenson William S. , Nurden Paquita , Watowich Stephanie S. , Justice Monica J.
Published: May 2007

A pivotal mediator of actin dynamics is the protein cofilin, which promotes filament severing and depolymerization, facilitating the breakdown of existing filaments, and the enhancement of filament growth from newly created barbed ends. It does so in concert with actin interacting protein 1 (Aip1), which serves to accelerate cofilin's activity. While progress has been made in understanding its biochemical functions, the physiologic processes the cofilin/Aip1 complex regulates, particularly in higher organisms, are yet to be determined. We have generated an allelic series for WD40 repeat protein 1 (Wdr1), the mammalian homolog of Aip1, and report that reductions in Wdr1 function produce a dramatic phenotype gradient. While severe loss of function at the Wdr1 locus causes embryonic lethality, macrothrombocytopenia and autoinflammatory disease develop in mice carrying hypomorphic alleles. Macrothrombocytopenia is the result of megakaryocyte maturation defects, which lead to a failure of normal platelet shedding. Autoinflammatory disease, which is bone marrow–derived yet nonlymphoid in origin, is characterized by a massive infiltration of neutrophils into inflammatory lesions. Cytoskeletal responses are impaired in Wdr1 mutant neutrophils. These studies establish an essential requirement for Wdr1 in megakaryocytes and neutrophils, indicating that cofilin-mediated actin dynamics are critically important to the development and function of both cell types.
Radioiodide imaging and radiovirotherapy of multiple myeloma using VSV(Δ51)-NIS, an attenuated vesicular stomatitis virus encoding the sodium iodide symporter gene
Authors: Goel Apollina , Carlson Stephanie K. , Classic Kelly L. , Greiner Suzanne , Naik Shruthi , Power Anthony T. , Bell John C. , Russell Stephen J.
Published: May 2007

Multiple myeloma is a radiosensitive malignancy that is currently incurable. Here, we generated a novel recombinant vesicular stomatitis virus [VSV(Δ51)-NIS] that has a deletion of methionine 51 in the matrix protein and expresses the human sodium iodide symporter (NIS) gene. VSV(Δ51)-NIS showed specific oncolytic activity against myeloma cell lines and primary myeloma cells and was able to replicate to high titers in myeloma cells in vitro. Iodide uptake assays showed accumulation of radioactive iodide in VSV(Δ51)-NIS–infected myeloma cells that was specific to the function of the NIS transgene. In bg/nd/xid mice with established subcutaneous myeloma tumors, administration of VSV(Δ51)-NIS resulted in high intratumoral virus replication and tumor regression. VSV-associated neurotoxicity was not observed. Intratumoral spread of the infection was monitored noninvasively by serial gamma camera imaging of 123I-iodide biodistribution. Dosimetry calculations based on these images pointed to the feasibility of combination radiovirotherapy with VSV(Δ51)-NIS plus 131I. Immunocompetent mice with syngeneic 5TGM1 myeloma tumors (either subcutaneous or orthotopic) showed significant enhancements of tumor regression and survival when VSV(Δ51)-NIS was combined with 131I. These results show that VSV(Δ51)-NIS is a safe oncolytic agent with significant therapeutic potential in multiple myeloma.
One-year acyclovir prophylaxis for preventing varicella-zoster virus disease after hematopoietic cell transplantation: no evidence of rebound varicella-zoster virus disease after drug discontinuation
Authors: Erard Veronique , Guthrie Katherine A. , Varley Cara , Heugel Judson , Wald Anna , Flowers Mary E. D. , Corey Lawrence , Boeckh Michael
Published: May 2007

No consensus exists on whether acyclovir prophylaxis should be given for varicella-zoster virus (VZV) prophylaxis after hematopoietic cell transplantation because of the concern of “rebound” VZV disease after discontinuation of prophylaxis. To determine whether rebound VZV disease is an important clinical problem and whether prolonging prophylaxis beyond 1 year is beneficial, we examined 3 sequential cohorts receiving acyclovir from day of transplantation until engraftment for prevention of herpes simplex virus reactivation (n = 932); acyclovir or valacyclovir 1 year (n = 1117); or acyclovir/valacyclovir for at least 1 year or longer if patients remained on immunosuppressive drugs (n = 586). In multivariable statistical models, prophylaxis given for 1 year significantly reduced VZV disease (P < .001) without evidence of rebound VZV disease. Continuation of prophylaxis beyond 1 year in allogeneic recipients who remained on immunosuppressive drugs led to a further reduction in VZV disease (P = .01) but VZV disease developed in 6.1% during the second year while receiving this strategy. In conclusion, acyclovir/valacyclovir prophylaxis given for 1 year led to a persistent benefit after drug discontinuation and no evidence of a rebound effect. To effectively prevent VZV disease in long-term hematopoietic cell transplantation survivors, additional approaches such as vaccination will probably be required.
Dickkopf-1 (DKK1) is a widely expressed and potent tumor-associated antigen in multiple myeloma
Authors: Qian Jianfei , Xie Jin , Hong Sungyoul , Yang Jing , Zhang Liang , Han Xiaohong , Wang Michael , Zhan Fenghuang , Shaughnessy John D. , Epstein Joshua , Kwak Larry W. , Yi Qing
Published: May 2007

The identification of novel tumor-associated antigens, especially those shared among patients, is urgently needed to improve the efficacy of immunotherapy for multiple myeloma (MM). In this study, we examined whether Dickkopf-1 (DKK1), a protein that is not expressed in most normal tissues but is expressed by tumor cells from almost all patients with myeloma, could be a good candidate. We identified and synthesized DKK1 peptides for human leukocyte antigen (HLA)–A*0201 and confirmed their immunogenicity by in vivo immunization in HLA-A*0201 transgenic mice. We detected, using peptidetetramers, low frequencies of DKK1 peptide-specific CD8-positive (CD8+) T cells in patients with myeloma and generated peptide-specific T-cell lines and clones from HLA-A*0201-positive (HLA-A*0201+) blood donors and patients with myeloma. These T cells efficiently lysed peptide-pulsed but not unpulsed T2 or autologous dendritic cells, DKK1-positive (DKK1+)/HLA-A*0201+ myeloma cell lines U266 and IM-9, and, more importantly, HLA-A*0201+ primary myeloma cells from patients. No killing was observed on DKK1+/HLA-A*0201-negative (HLA-A*0201−) myeloma cell lines and primary myeloma cells or HLA-A*0201+ normal lymphocytes, including B cells. These results indicate that these T cells were potent cytotoxic T cells and recognized DKK1 peptides naturally presented by myeloma cells in the context of HLA-A*0201 molecules. Hence, our study identifies DKK1 as a potentially important antigen for immunotherapy in MM.
Live imaging of Drosophilagonad formation reveals roles for Six4 in regulating germline and somatic cell migration
Authors: Clark Ivan BN , Jarman Andrew P , Finnegan David J
Published: May 2007

Background

Movement of cells, either as amoeboid individuals or in organised groups, is a key feature of organ formation. Both modes of migration occur during Drosophila embryonic gonad development, which therefore provides a paradigm for understanding the contribution of these processes to organ morphogenesis. Gonads of Drosophila are formed from three distinct cell types: primordial germ cells (PGCs), somatic gonadal precursors (SGPs), and in males, male-specific somatic gonadal precursors (msSGPs). These originate in distinct locations and migrate to associate in two intermingled clusters which then compact to form the spherical primitive gonads. PGC movements are well studied, but much less is known of the migratory events and other interactions undergone by their somatic partners. These appear to move in organised groups like, for example, lateral line cells in zebra fish or Drosophila ovarian border cells.

Results

We have used time-lapse fluorescence imaging to characterise gonadal cell behaviour in wild type and mutant embryos. We show that the homeodomain transcription factor Six4 is required for the migration of the PGCs and the msSGPs towards the SGPs. We have identified a likely cause of this in the case of PGCs as we have found that Six4 is required for expression of Hmgcr which codes for HMGCoA reductase and is necessary for attraction of PGCs by SGPs. Six4 affects msSGP migration by a different pathway as these move normally in Hmgcr mutant embryos. Additionally, embryos lacking fully functional Six4 show a novel phenotype in which the SGPs, which originate in distinct clusters, fail to coalesce to form unified gonads.

Conclusion

Our work establishes the Drosophila gonad as a model system for the analysis of coordinated cell migrations and morphogenesis using live imaging and demonstrates that Six4 is a key regulator of somatic cell function during gonadogenesis. Our data suggest that the initial association of SGP clusters is under distinct control from the movements that drive gonad compaction.
STATc is a key regulator of the transcriptional response to hyperosmotic shock
Authors: Na Jianbo , Tunggal Budi , Eichinger Ludwig
Published: May 2007

Background

Dictyostelium discoideum is frequently subjected to environmental changes in its natural habitat, the forest soil. In order to survive, the organism had to develop effective mechanisms to sense and respond to such changes. When cells are faced with a hypertonic environment a complex response is triggered. It starts with signal sensing and transduction and leads to changes in cell shape, the cytoskeleton, transport processes, metabolism and gene expression. Certain aspects of the Dictyostelium osmotic stress response have been elucidated, however, no comprehensive picture was available up to now.

Results

To better understand the D. discoideum response to hyperosmotic conditions, we performed gene expression profiling using DNA microarrays. The transcriptional profile of cells treated with 200 mM sorbitol during a 2-hour time course revealed a time-dependent induction or repression of 809 genes, more than 15% of the genes on the array, which peaked 45 to 60 minutes after the hyperosmotic shock. The differentially regulated genes were applied to cluster analysis and functional annotation using gene GO terms. Two main responses appear to be the down-regulation of the metabolic machinery and the up-regulation of the stress response system, including STATc. Further analysis of STATc revealed that it is a key regulator of the transcriptional response to hyperosmotic shock. Approximately 20% of the differentially regulated genes were dependent on the presence of STATc.

Conclusion

At least two signalling pathways are activated in Dictyostelium cells subjected to hypertonicity. STATc is responsible for the transcriptional changes of one of them.
bZIPDB : A database of regulatory information for human bZIP transcription factors
Authors: Ryu Taewoo , Jung Juhyun , Lee Sunjae , Nam Ho Jung , Hong Sun Woo , Yoo Jae Wook , Lee Dong-ki , Lee Doheon
Published: May 2007

Background

Basic region-leucine zipper (bZIP) proteins are a class of transcription factors (TFs) that play diverse roles in eukaryotes. Malfunctions in these proteins lead to cancer and various other diseases. For detailed characterization of these TFs, further public resources are required.

Description

We constructed a database, designated bZIPDB, containing information on 49 human bZIP TFs, by means of automated literature collection and manual curation. bZIPDB aims to provide public data required for deciphering the gene regulatory network of the human bZIP family, e.g., evaluation or reference information for the identification of regulatory modules. The resources provided by bZIPDB include (1) protein interaction data including direct binding, phosphorylation and functional associations between bZIP TFs and other cellular proteins, along with other types of interactions, (2) bZIP TF-target gene relationships, (3) the cellular network of bZIP TFs in particular cell lines, and (4) gene information and ontology. In the current version of the database, 721 protein interactions and 560 TF-target gene relationships are recorded. bZIPDB is annually updated for the newly discovered information.

Conclusion

bZIPDB is a repository of detailed regulatory information for human bZIP TFs that is collected and processed from the literature, designed to facilitate analysis of this protein family. bZIPDB is available for public use at http://biosoft.kaist.ac.kr/bzipdb.
Down-regulation of human topoisomerase IIα expression correlates with relative amounts of specificity factors Sp1 and Sp3 bound at proximal and distal promoter regions
Authors: Williams Amram O , Isaacs Richard J , Stowell Kathryn M
Published: May 2007

Background

Topoisomerase IIα has been shown to be down-regulated in doxorubicin-resistant cell lines. The specificity proteins Sp1 and Sp3 have been implicated in regulation of topoisomerase IIα transcription, although the mechanism by which they regulate expression is not fully understood. Sp1 has been shown to bind specifically to both proximal and distal GC elements of the human topoisomerase IIα promoter in vitro, while Sp3 binds only to the distal GC element unless additional flanking sequences are included. While Sp1 is thought to be an activator of human topoisomerase IIα, the functional significance of Sp3 binding is not known. Therefore, we sought to determine the functional relationship between Sp1 and Sp3 binding to the topoisomerase IIα promoter in vivo. We investigated endogenous levels of Sp1, Sp3 and topoisomerase IIα as well as binding of both Sp1 and Sp3 to the GC boxes of the topoisomerase IIα promoter in breast cancer cell lines in vivo after short term doxorubicin exposure.

Results

Functional effects of Sp1 and Sp3 were studied using transient cotransfection assays using a topoisomerase IIα promoter reporter construct. The in vivo interactions of Sp1 and Sp3 with the GC elements of the topoisomerase IIα promoter were studied in doxorubicin-treated breast cancer cell lines using chromatin immunoprecipitation assays. Relative amounts of endogenous proteins were measured using immunoblotting. In vivo DNA looping mediated by proteins bound at the GC1 and GC2 elements was studied using the chromatin conformation capture assay. Both Sp1 and Sp3 bound to the GC1 and GC2 regions. Sp1 and Sp3 were transcriptional activators and repressors respectively, with Sp3 repression being dominant over Sp1-mediated activation. The GC1 and GC2 elements are linked in vivo to form a loop, thus bringing distal regulatory elements and their cognate transcription factors into close proximity with the transcription start site.

Conclusion

These observations provide a mechanistic explanation for the modulation of topoisomerase IIα and concomitant down-regulation that can be mediated by topoisomerase II poisons. Competition between Sp1 and Sp3 for the same cognate DNA would result in activation or repression depending on absolute amounts of each transcription factor in cells treated with doxorubicin.
Rad9 modulates the P21
WAF1
pathway by direct association with p53
Authors: Ishikawa Kazuhiro , Ishii Hideshi , Murakumo Yoshiki , Mimori Koshi , Kobayashi Masahiko , Yamamoto Ken-ichi , Mori Masaki , Nishino Hiroshi , Furukawa Yusuke , Ichimura Keiichi
Published: May 2007

Background

Previous studies suggest that human RAD9 (hRad9), encoding a DNA damage checkpoint molecule, which is frequently amplified in epithelial tumor cells of breast, lung, head and neck cancer, participates in regulation of the tumor suppressor p53-dependent transactivation of pro-survival P21

WAF1
. This study examined the exact mechanism of the hRad9 function, especially through the phosphorylation of the C-terminus, in the transcription regulation of P21

WAF1
.

Results

The transfection of phosphorylation-defective hRAD9 mutants of C-terminus resulted in reduction of the p53-dependent P21

WAF1
transactivation; the knockdown of total hRad9 elicited an increased P21

WAF1
mRNA expression. Immunoprecipitation and a ChIP assay showed that hRad9 and p53 formed a complex and both were associated with two p53-consensus DNA-binding sequences in the 5' region of P21

WAF1
gene. The association was reduced in the experiment of phosphorylation-defective hRAD9 mutants.

Conclusion

The present study indicates the direct involvement of hRad9 in the p53-dependent P21

WAF1
transcriptional mechanism, presumably via the phosphorylation sites, and alterations of the hRad9 pathway might therefore contribute to the perturbation of checkpoint activation in cancer cells.
The standardized surgical approach improves outcome of gallbladder cancer
Authors: Scheingraber Stefan , Justinger Christoph , Stremovskaia Tatiana , Weinrich Malte , Igna Dorian , Schilling Martin K
Published: May 2007

Background

The objective of this study was to examine the extent of surgical procedures, pathological findings, complications and outcome of patients treated in the last 12 years for gallbladder cancer.

Methods

The impact of a standardized more aggressive approach compared with historical controls of our center with an individual approach was examined. Of 53 patients, 21 underwent resection for cure and 32 for palliation.

Results

Overall hospital mortality was 9% and procedure related mortality was 4%. The standardized approach in UICC stage IIa, IIb and III led to a significantly improved outcome compared to patients with an individual approach (Median survival: 14 vs. 7 months, mean+/-SEM: 26+/-7 vs. 17+/-5 months, p = 0.014). The main differences between the standardized and the individual approach were anatomical vs. atypical liver resection, performance of systematic lymph dissection of the hepaticoduodenal ligament and the resection of the common bile duct.

Conclusion

Anatomical liver resection, proof for bile duct infiltration and, in case of tumor invasion, radical resection and lymph dissection of the hepaticoduodenal ligament are essential to improve outcome of locally advanced gallbladder cancer.
Distinguishing enzymes using metabolome data for the hybrid dynamic/static method
Authors: Ishii Nobuyoshi , Nakayama Yoichi , Tomita Masaru
Published: May 2007

Background

In the process of constructing a dynamic model of a metabolic pathway, a large number of parameters such as kinetic constants and initial metabolite concentrations are required. However, in many cases, experimental determination of these parameters is time-consuming. Therefore, for large-scale modelling, it is essential to develop a method that requires few experimental parameters. The hybrid dynamic/static (HDS) method is a combination of the conventional kinetic representation and metabolic flux analysis (MFA). Since no kinetic information is required in the static module, which consists of MFA, the HDS method may dramatically reduce the number of required parameters. However, no adequate method for developing a hybrid model from experimental data has been proposed.

Results

In this study, we develop a method for constructing hybrid models based on metabolome data. The method discriminates enzymes into static modules and dynamic modules using metabolite concentration time series data. Enzyme reaction rate time series were estimated from the metabolite concentration time series data and used to distinguish enzymes optimally for the dynamic and static modules. The method was applied to build hybrid models of two microbial central-carbon metabolism systems using simulation results from their dynamic models.

Conclusion

A protocol to build a hybrid model using metabolome data and a minimal number of kinetic parameters has been developed. The proposed method was successfully applied to the strictly regulated central-carbon metabolism system, demonstrating the practical use of the HDS method, which is designed for computer modelling of metabolic systems.
Femoral tunnel placement in anterior cruciate ligament reconstruction: rationale of the two incision technique
Authors: Garofalo Raffaele , Moretti Biagio , Kombot Cyril , Moretti Lorenzo , Mouhsine Elyazid
Published: May 2007

Endoscopic anterior cruciate ligament (ACL) reconstruction can be performed through one-incision or two-incision technique. The current one-incision endoscopic ACL single bundle reconstruction techniques attempt to perform an isometric repair placing the graft along the roof of the intercondylar notch, anterior and superior to the native ACL insertion. However the ACL isometry is a theoretical condition, and has not stood up to detailed testing and investigation. Moreover this type of reconstruction results in a vertically oriented non-anatomic graft, which is able to control anterior tibial translation but not the rotational component of the instability. Femoral tunnel obliquity has a great effect on rotational stability. To improve the obliquity of graft, an anatomical ACL reconstruction should be attempt. Anatomical insertion of ACL on the femur lies very low in the notch, spreading between 11 and 9–8 o'clock position and the center lies lower than at 11 o'clock position. Femoral aiming devices through the tibial tunnel aim at an isometric placement, and they do not aim at an anatomic position of the graft. Also, a placement of tunnel in a position of 11 o'clock is unable to restore rotational stability. The two-incision technique, with the possibility to position femoral tunnel independently by tibial tunnel, allows us to place femoral tunnel entrance in a position of 10 'clock that can most accurately reproduce the anatomic behaviour of the ACL and can potentially improve the response of the graft to rotatory loads. This positioning results in a more oblique graft placement, avoiding problem related to PCL impingement during knee flexion. Further studies are required to understand if this kind of reconstruction can ameliorate proprioception as well as clinical outcome at a long-term follow-up.
Phase I/II Study of an Anti-CD30 Monoclonal Antibody (MDX-060) in Hodgkin's Lymphoma and Anaplastic Large-Cell Lymphoma
Authors: Ansell Stephen M. , Horwitz Steven M. , Engert Andreas , Khan Khuda Dad , Lin Thomas , Strair Roger , Keler Tibor , Graziano Robert , Blanset Diann , Yellin Michael , Fischkoff Steven , Assad Albert , Borchmann Peter
Published: May 2007

Purpose

MDX-060 is a human anti-CD30 immunoglobulin (Ig) G1κ monoclonal antibody that inhibits growth of CD30-expressing tumor cells in preclinical models. To determine the safety, maximum-tolerated dose (MTD), and efficacy of MDX-060 in patients with relapsed or refractory CD30+ lymphomas, sequential phase I and II studies were performed.

Patients and Methods

In the phase I portion, MDX-060 was administered intravenously at doses of 0.1, 1, 5, or 10 mg/kg weekly for 4 weeks to cohorts of three to six patients. Twenty-one patients—16 with Hodgkin's lymphoma (HL), three with anaplastic large-cell lymphoma (ALCL), and two with CD30+ T-cell lymphoma—were enrolled. Because of the lack of a defined MTD or dose-response correlation, the phase II portion was amended to include several dose levels. In the phase II portion, an additional 51 patients, 47 with HL and four with ALCL, were treated at doses of 1, 5, 10, and 15 mg/kg.

Results

MDX-060 was well tolerated, and an MTD has not been identified. Only 7% of patients experienced grade 3 or 4 treatment-related adverse events. Among the 72 patients treated, clinical responses were observed in six. Twenty-five patients had stable disease, including five who remained free from progression 1 year after treatment.

Conclusion

MDX-060 was well tolerated at doses up to 15 mg/kg. MDX-060 has limited activity as a single agent, but the minimal toxicity observed and the significant proportion of patients with stable disease suggests that further study of MDX-060 in combination with other therapies is warranted.
Myeloablative Therapy With Autologous Bone Marrow Transplantation for Follicular Lymphoma at the Time of Second or Subsequent Remission: Long-Term Follow-Up
Authors: Rohatiner Ama Z.S. , Nadler Lee , Davies Andrew J. , Apostolidis John , Neuberg Donna , Matthews Janet , Gribben John G. , Mauch Peter M. , Lister T. Andrew , Freedman Arnold S.
Published: May 2007

Purpose

The aim of this retrospective analysis was to determine the outcome of patients with follicular lymphoma who received myeloablative therapy supported by autologous bone marrow transplantation as consolidation of second or subsequent remission, with a minimum follow-up of 12 years.

Patients and Methods

One hundred twenty-one adults received cyclophosphamide (CY) and total-body irradiation (TBI) supported by autologous bone marrow transplantation, with the marrow mononuclear cell fraction having been treated with monoclonal antibodies and complement. Data from St Bartholomew's Hospital and Dana-Farber Cancer Institute were combined for the purpose of this analysis because the patients were treated in an identical manner.

Results

Fifty-seven patients are alive, 41 without progression between 9 and 19 years; 64 patients have died, 20 without progression. With a median follow-up of 13.5 years, 60 patients have developed recurrent lymphoma. There is an apparent plateau on the remission duration curve at 48% at 12 years. Survival of patients treated in second remission was significantly longer than the survival of patients treated later in the course of the illness. Both remission duration and overall survival were also significantly longer for patients treated in second remission compared with an age-matched, remission-matched group of patients treated at St Bartholomew's Hospital before the introduction of this treatment. However, use of CY+TBI was associated with a significant risk of secondary myelodysplasia and secondary acute myeloblastic leukemia, resulting in 15 patient deaths.

Conclusion

These mature data confirm that prolonged freedom from recurrence may be achieved with myeloablative therapy and that a plateau on the curve seems to emerge with long follow-up.
Tamoxifen, Soy, and Lifestyle Factors in Asian American Women With Breast Cancer
Authors: Wu Anna H. , Pike Malcolm C. , Williams Lee D. , Spicer Darcy , Tseng Chiu-Chen , Churchwell Mona I. , Doerge Daniel R.
Published: May 2007

Purpose

Soy foods have been a staple in Asia for centuries but the consumption of this food in the West is recent. Intake of soy among women at high risk for or with breast cancer has become a public health concern because genistein, a major component of soy, has weak estrogenic effects on breast epithelium, and has been found to negate the benefit of tamoxifen in some animal and in vitro studies.

Patients and Methods

We conducted a cross-sectional study in Asian Americans with breast cancer who were tamoxifen users (n = 380) to investigate the association between soy intake and circulating levels of tamoxifen and its metabolites (N-desmethyl tamoxifen [N-DMT], 4-hydroxytamoxifen [4-OHT], and 4-hydroxy-N-desmethyl-tamoxifen [endoxifen]).

Results

Serum levels of tamoxifen or its metabolites were unrelated to self-reported intake of soy or serum levels of isoflavones. Blood levels of tamoxifen were 81% higher in postmenopausal women age 65 or older compared with premenopaual women age 45 or younger (P = .005); similar patterns of results were observed for the tamoxifen metabolites. Levels of N-DMT were 27% (P = .03) lower among women in the highest tertile of body mass index (BMI, > 24.4 kg/m2) compared with those in the lowest category (BMI ≤ 21.5). Women who used hypertensive medications had higher levels of tamoxifen (P = .02) and N-DMT (P = .04) compared with nonusers.

Conclusion

We found no evidence that soy intake adversely affected levels of tamoxifen or its metabolites. However, age, menopausal status, BMI, and use of hypertensive medications significantly influenced circulating levels of tamoxifen and its metabolites in this population.
The use of proteomics to identify novel therapeutic targets for the treatment of disease
Authors: Moseley Fleur L , Bicknell Katrina A , Marber Michael S , Brooks Gavin
Published: May 2007

The completion of the Human Genome Project has revealed a multitude of potential avenues for the identification of therapeutic targets. Extensive sequence information enables the identification of novel genes but does not facilitate a thorough understanding of how changes in gene expression control the molecular mechanisms underlying the development and regulation of a cell or the progression of disease. Proteomics encompasses the study of proteins expressed by a population of cells, and evaluates changes in protein expression, post-translational modifications, protein interactions, protein structure and splice variants, all of which are imperative for a complete understanding of protein function within the cell. From the outset, proteomics has been used to compare the protein profiles of cells in healthy and diseased states and as such can be used to identify proteins associated with disease development and progression. These candidate proteins might provide novel targets for new therapeutic agents or aid the development of assays for disease biomarkers. This review provides an overview of the current proteomic techniques available and focuses on their application in the search for novel therapeutic targets for the treatment of disease.
Cyclodextrin microparticles for drug delivery to the posterior segment of the eye: aqueous dexamethasone eye drops
Authors: Loftsson Thorsteinn , Hreinsdóttir Dagný , Stefánsson Einar
Published: May 2007

Delivery of steroids to the retina is currently undertaken with invasive injections into the vitreous cavity. This paper describes a non-invasive method to deliver steroids in therapeutic levels to the retina in rabbits. Dexamethasone was formulated as somewhat water-soluble dexamethasone/γ-cyclodextrin (γCD) microparticles in a low-viscosity aqueous eye drop suspension. The mean (± standard deviation) diameter of the particles was 20.4 ± 10.3 μm, with no particles larger than 60 μm. The aqueous suspension formulation was tested in rabbits and compared with an aqueous dexamethasone eye drop solution containing randomly methylated β-cyclodextrin (RMβCD). The dexamethasone concentration was identical in both formulations (15 mg mL−1). The drug was administered to the left eye but determined in both eyes. The amount reaching different eye tissues via the topical route was determined by subtracting the amount found in the right eye from the amount found in the left eye. Two hours after single application of the dexamethasone/γCD eye drops to rabbits the mean (± s.d.) concentration in vitreous was 29 ± 16 ng g−1, 86% of which reached vitreous via the topical route and in retina the concentration was 57 ± 22 ng g−1 (49% via topical route). For the RMβCD the values were 22.6 ± 9 and 66 ± 49 ng g−1 (73 and 14% via topical route), respectively. These steroid levels are comparable with the dexamethasone concentration achieved 1 month after intravitreal injection. The aqueous dexamethasone/γCD eye drop formulation was chemically stable during 7 months storage and well tolerated with no visible short-term side effects.
Analysis of eupatilin-human serum albumin interactions by means of spectroscopic and computational modelling
Authors: Tang Jianghong , Lian Ning , Bi Chenglu , Li Weihua
Published: May 2007

The interaction of eupatilin (5,7-dihydroxy-3′,4′,6-trimethoxyflavone) with human serum albumin (HSA) was studied at simulative physiological pH, with a HSA concentration of 3.0 times 10−6 mol L−1 and eupatilin concentrations over the range of 6.0 times 10−6 to 1.9 times 10−5 mol L−1. Fluorescence spectroscopy in combination with UV absorption spectroscopy and Fourier transform infrared (FTIR) spectroscopy were used to study the binding properties (including binding mechanism, the binding constants, the number of binding sites and the binding mode) of the interaction of eupatilin with HSA and the effect of this drug on HSA conformation changes. According to the Scatchard equation there was only one class of binding site that could bind to HAS; the binding constants were 1.53 times 105, 1.20 times 105, 1.05 times 105, 0.87 times 105 L mol−1 at temperatures of 287, 298, 310 and 318 K, respectively. The FTIR spectra revealed that the protein secondary structure changed, with reductions in α-helices of about 3.65% at a drug to protein molar ratio of 3. The thermodynamic analysis (enthalpy and entropy change: ΔH0 and ΔS0) and the computational modelling study indicated that hydrophobic force played an important role in eupatilin-HSA complex stabilization, and eupatilin could bind within the subdomain IIA of HSA.
Physicochemical characterization of solid dispersions of three antiepileptic drugs prepared by solvent evaporation method
Authors: Douroumis Dionysios , Bouropoulos Nikolaos , Fahr Alfred
Published: May 2007

We have investigated the solid dispersion and dissolution profiles of three antiepileptic drugs (carbamazepine (CBZ), oxcarbazepine (OXC) and rufinamide (RFN)) with different aqueous solubilities, prepared by the solvent evaporation method. Solid dispersions of the three drugs in hydroxy-propylmethylcellulose (HPMC), with drug:polymer ratios of 1:4, were prepared and characterized by differential scanning calorimetry (DSC), Fourier transformation infrared (FTIR) spectroscopy, X-ray diffraction (XRD) and scanning electron microscopy. The release mechanism was also investigated and the kinetic order of the solid dispersions was evaluated. It appeared that the dissolution behaviour depended on the physicochemical properties of the drug and drug-polymer interactions. DSC thermographs showed amorphous forms for all drugs confirmed by XRD patterns. The FTIR spectra of CBZ and OXC demonstrated drug interactions with HPMC through hydrogen polymer bonds. Thus, solid dispersions of these drugs had an improved dissolution profile. In contrast, solid dispersions of RUF showed modest enhancement of dissolution, suggesting negligible drug-polymer interactions. The different dissolution behaviour is attributed to the extent of interactions between the polymer hydroxyl group and the drug amide groups.