bluuebunny/crossref_metadata_2025 huggingface dataset:
Single‐Dose and Multiple‐Dose Pharmacokinetics and Safety of Telbivudine After Oral Administration in Healthy Chinese Subjects
Authors: Hu Pei , Jiang Ji , Wang Hongyun , Pietropaolo Keith , Chao George C. , Brown Nathaniel A. , Zhou Xiao‐Jian
Published: August 2006

The pharmacokinetics of telbivudine, an L‐nucleoside with potent activity against hepatitis B virus, was assessed in 42 healthy Chinese volunteers. Subjects were assigned to receive a single oral dose of 200, 400, or 800 mg telbivudine or repeat doses of 600 mg/d. Telbivudine was absorbed rapidly and exhibited dose‐related plasma exposure. After reaching maximum concentration (Cmax) at a median time of 2.0 to 2.5 hours, plasma disposition of the drug was biphasic with a mean terminal half‐life ranging from 39.4 to 49.1 hours. Telbivudine accumulated slightly after repeat doses, and steady state was reached after 5 to 6 consecutive doses of 600 mg/d. The mean steady‐state Cmax and area under the plasma concentration–time curve over the dosing interval of telbivudine 600 mg were 3.7 μg/mL and 26.1 μg·h/mL, respectively. Cumulative urinary excretion of telbivudine over 32 hours represented 24.4% of the administered dose, with a mean renal clearance of 6.6 L/h. Telbivudine was well tolerated in the studied dose range in healthy Chinese subjects, with no pattern of dose‐related clinical or laboratory adverse events.
Single‐Dose Pharmacokinetics of Varenicline, a Selective Nicotinic Receptor Partial Agonist, in Healthy Smokers and Nonsmokers
Authors: Faessel Hélène M. , Smith Bill J. , Gibbs Megan A. , Gobey Jason S. , Clark David J. , Burstein Aaron H.
Published: August 2006

Varenicline is a novel and selective α4β2 nicotinic receptor partial agonist that is under development for smoking cessation. The primary objectives of this double‐blind, placebo‐controlled, single‐dose, dose‐escalation study were to determine the clinical pharmacology of single doses of varenicline in healthy smokers and nonsmokers under fed and fasted conditions and to determine the clinical pharmacology of varenicline administered in the morning and in the evening to smokers. Within each subject group, 4 subjects were randomized to varenicline and 2 subjects to placebo. Subjects received one single oral administration of varenicline or placebo: 6 doses (0.01, 0.03, 0.1, 0.3, 1.0, and 3.0 mg) were investigated in nonsmokers and 7 doses in smokers (0.01, 0.03, 0.1, 0.3, 1.0, 3.0, and 10.0 mg). Varenicline was well tolerated after single doses up to 3.0 mg in smokers and 1.0 mg in nonsmokers. Nausea and vomiting at doses above 3.0 mg in smokers and 1.0 mg in nonsmokers were dose limiting. Systemic exposure to varenicline and pharmacokinetic variability were similar between smokers and nonsmokers. Coadministration with food, smoking restriction, and time‐of‐day dosing did not affect the pharmacokinetics of varenicline.
Pharmacokinetics of Dapoxetine, a New Treatment for Premature Ejaculation: Impact of Age and Effects of a High‐Fat Meal
Authors: Dresser Mark J. , Kang Dongwoo , Staehr Peter , Gidwani Shalini , Guo Cindy , Mulhall John P. , Modi Nishit B.
Published: August 2006

Dapoxetine is being developed as a treatment for premature ejaculation and has demonstrated rapid absorption and elimination in previous pharmacokinetic studies. Two open‐label studies were conducted in healthy men: a parallel‐group pharmacokinetic and safety study in young and elderly men and a randomized crossover food‐effect study. Maximal plasma dapoxetine concentrations (Cmax) were similar in young and elderly men (338 and 310 ng/mL, respectively), as were the corresponding area under the plasma concentration versus time curve (AUC) values (2040 and 2280 ng·h/mL, respectively). When coadministered with food, Cmax was reduced by 11% (398 vs 443 ng/mL in the fed and fasted states, respectively), and the peak was delayed by approximately 30 minutes, indicating that food slowed the rate of absorption; however, systemic exposure to dapoxetine (ie, AUC) was not affected by food consumption. Thus, age or consumption of a high‐fat meal has only a modest impact on dapoxetine pharmacokinetics in healthy men.
Academic Exchanges and Transnational Relations
Authors: Alzugaray Carlos
Published: August 2006

Academic exchanges (scientific, educational, and cultural), understood as a form of transnational collaboration between the intellectual communities of two countries, play an important role in international relations and can contribute to the eventual resolution of conflicts between nations. In the case of Cuba and the United States, the development of exchanges on a more or less regular basis has coincided with periods of less tension in bilateral relations, and exchanges have been an important factor in the pursuit of normalization. The present situation in Cuba-U.S. relations is not normal and does not contribute in any way to the mutual benefit of the two countries and peoples. Fostering such exchanges will contribute to the mutual understanding of contradictory interests and to the realistic aspiration of the two societies’ someday coexisting in peace and harmony.
Academic Exchange between Cuba and the United States
Authors: Martínez Milagros
Published: August 2006

Examination of the origin and evolution of academic exchange between Cuba and the United States, with emphasis on the period since 1959, reveals a close relationship between that exchange and both the conflict between the two nations and the development of Cuban studies in the United States. This review suggests the need for academics in the two countries to take steps to preserve what has been achieved and to pursue alternative means for continuing their cooperation.
The Bush Administration and Academic and Educational Exchange between Cuba and the United States
Authors: Mariño Soraya Castro
Published: August 2006

A new set of regulations has been implemented by the Bush administration to limit academic, cultural, and educational exchange between Cuba and the United States. The United States’s political priority after the 9/11 attacks, the so-called war on terrorism, could have fostered cooperation between the two countries. Instead—and against the logic of collaborative policies—the Bush administration has taken a series of measures that further threaten the precarious bilateral interactions. As a result, academic and educational exchange has been seriously affected.
National Security, the State, and the Politics of U.S.-Cuba Educational Exchange
Authors: Lutjens Sheryl L.
Published: August 2006

In the context of the global war on terror, the political logic of U.S. Cuba policy seems oddly constant. Despite the renovation of the national security state and U.S. global strategy, and the expanded constellation of domestic interests at play in the Clinton-era policy of people-to-people exchange, long-lived hostility toward Castro and intractable reliance on economic sanctions and threats seem to characterize the post-9/11 Cuba policy of the Bush administration. Yet striking changes have in fact occurred, among them the radical restriction of travel and remittances to Cuba by Cuban-Americans and the limiting of academic exchange between Cuba and the United States. An exploration of Bush’s Cuba policy and its implementation in the homeland security state reveals the tensions between antiterrorism and anti-Castroism.
Teachers and Socio-educational Entrepreneurship
Authors: Chand Vijaya Sherry , Amin-Choudhury Geeta
Published: August 2006

This article examines how teachers who have achieved their educational goals in rural contexts of socio-economic and educational deprivation have redefined their roles using socio-educationally entrepreneurial practices, and consequently, have created an identity of ‘competence’ for themselves. We identify social entrepreneurship—developing self-defined extra-school roles—as the first step such teachers take to construct for themselves an identity of competence in social leadership. This competence helps them build an ‘educational domain consensus’ among relevant stakeholders. The development of local, teacher-initiated, community networks accompanies the building of this consensus. Incorporating the expectations conveyed to them by this community network into the formally given framework of professional teaching skills helps the teachers develop a new sense of themselves as competent educational leaders. The new identity, which is defined by a mix of educational and social leadership qualities, commands respect, invites appreciation and communicates moral authority. It helps teachers move beyond enrolment and attendance concerns to a renewed focus on within-classroom activities.
Recasting Job Creation Strategies in Developing Regions
Authors: Eid Florence
Published: August 2006

Efforts to develop private equity finance in some countries in the Middle East and North Africa (MENA) are yielding job creation rates up to five times the average rate of labour market growth in the region. This article argues that we should learn and generalise from this experience and from related experiences in other parts of the world because of the pressing need for regions like MENA to promote employment-generating growth. The paper draws on illustrative developments in the financial sector, education and business in MENA to recommend a new generation of reforms that promote entrepreneurial finance because of its high job-creation potential for emerging markets. Requisite reforms include proactive new financial institutions and incentives, financial instruments such as private equity funds, and an array of complementary educational programmes. The task of providing the right macro-economic and regulatory environment for the private sector is no less important. However, it is no longer sufficient. Regional private equity industry surveys conducted for this article assess the developments across countries in MENA, and relay the sector's need for proactive reforms that support it. The article also shows how developments in entrepreneurial finance in MENA coincide with a growing interest over the past fifteen years in research, business schools and the financial sector in furthering ideas, designing educational programmes and creating funds that promote the study and practice of entrepreneurship. It explains how in research, a paradigm shift in economic theory has renewed interest in the entrepreneurial firm from a micro perspective, in contrast to the neo-classical conception of the firm as a black box production function. It also shows that international financial market interest in private equity finance does not seem to have abated with the recent market bust. These factors explain the growing attention to the arguably ‘old’ concept of entrepreneurship. The article concludes by identifying priority areas for future policy and research.
Networking and New Venture Resource Strategies
Authors: Ramachandran K. , Ray Sougata
Published: August 2006

While the network theory and the resource-based view of the firm has emerged as a dominant paradigm of management research, entrepreneurship researchers continue to show limited interest in studying resource strategies and the role of network in building dynamic capabilities in entrepreneurial start-ups. Scant discussion is available in extant literature on the dynamics of new venture resource strategy to explain how entrepreneurs continuously augment, manage and develop resources to match the shifting product-market strategy and use networks in doing so on a sustainable basis. This article, based on an analysis of two Information Technology (IT) start-ups, explores the innovative and dynamic resource and networking strategies such firms follow. An attempt has been made to conceptualise and explain how these firms maintain flexibility in resources by using the network mode of organisation in order to avoid strategic rigidity and craft strategies that are suited to the high velocity environment. Several propositions have been developed and practical implications have been drawn in this regard.
Intention for Entrepreneurship among Students in India
Authors: Bhandari Narendra C.
Published: August 2006

The purpose of this research was to study what a group of university students in India intended to do upon completion of their college education: start their own business (become entrepreneurs) or work for someone else? A 62-item question-naire was administered to the first year students of the Faculty of Commerce and Management Studies at Jai Narain Vyas University, Jodhpur, India. Of the 186 questionnaires returned, 100 were usable for this study. From the results of chi-square tests, of the eighteen independent variables, only two (luck and to lead other people) were found to have significant relationships with the dependent variable (to start your own business). According to results of factor analysis, six variables (to lead other people, to be my own boss, to put my innovative ideas into practice, determination, personal challenge and non-business education) were found to relate to the dependent variable. Finally, the logistic regression analysis showed that these six factors have a 92.35 per cent predictive value.
Entrepreneurship among Diasporic Communities
Authors: Bal Gurpreet
Published: August 2006

A comparative examination of two communities of India, namely, the Patidars of Gujarat and the Jats of Punjab, who constitute a majority in the Indian diaspora, reveals that both these communities share certain features such as landownership, middle caste status and a dominant caste position besides some socio-cultural similarities. Despite their common background, each has performed differently in foreign countries. The nature and streams of their immigration patterns differ. In the case of Patidars, it is a step migration while amongst the Jats the pioneers were ex-soldiers. The innovativeness and entrepreneurship of the Patidars significantly contributed to the economic development of the host countries. The Jats—the most progressive community—are found in almost all parts of the globe. They have largely taken up agricultural and industrial labour activities. They invariably invest their surplus money in buying some agricultural land. The differential performance of two communities points towards their different attributes, orientations towards work, work ideologies and primordial ties such as sense of family and kinship networks.
SMEs, Growth and Entrepreneurship
Authors: Mumby-Croft Roger , Brown Reva Berman
Published: August 2006

The article uses a case study of marketing entrepreneurialism to focus on issues concerning the role and reality of the entrepreneur in society in order to seek in-sights into the way market entrepreneurialism as a contemporary experience might be conceptualised through various epistemological narratives. These concerns are brought into relief through a compelling story of an entrepreneurial rise and fall in the Grimsby (UK) fish industry in the 1980s. The article highlights issues such as the conflict between moral individualism which gives market entrepreneurship its cultural and ethical basis and the need for social responsibility by, and towards, entrepreneurial businesses, and considers how we can better understand the market entrepreneur operating within these paradoxical cultural forces.
The Mold That Almost Ate the Principal
Authors: Barry Wayne , Bishop Chuck , Byars Jennifer
Published: August 2006

New-building mold was a bane for many home construction companies and new homeowners during the 1990s. It was not unusual to read or watch the news and see the tragedy played out in one’s local community. Untold, however, is the story of the toll new-building mold can take on school systems and their principals, especially as these mold problems might be a smokescreen or lightning rod for other things that go on in the daily life of a learning community. Griswold Elementary School’s problem with mold illustrates several phenomena for school administrators, namely, that organizations can be unwieldy and unpredictable at times, schools are highly symbolic and political structures, school reform involves the whole community, context is important for understanding and guiding organizational problem-solving efforts, effective communication is critical to effective organizational functioning, authority structures are important for accomplishing many tasks, and thankfully, organizations can learn from their own behavior.
The Plains City Story
Authors: van Olphen Marcela , Rios Francisco , Berube William , Dexter Robin , McCarthy Robert
Published: August 2006

This case study portrays a contemporary phenomenon that affects many U.S. school districts. Specifically, the authors address the challenges that the superintendent of the Plains City school district faced as a result of a change in the demographic distribution of his district. The gradual development of the pig farming industry in Plains City generated an increasing demand for workers. Because of this development, the number of Mexican students in the Plains City school district increased significantly. The authors present an account of some of the actions taken to promote dialogue and to decrease the tension that was generated as a result of the social changes in the community.
The Technology Balance Beam
Authors: Coulson Eddie K.
Published: August 2006

“The Technology Balance Beam” is designed to question the role of technology within school districts. This case study chronicles a typical school district in relation to the school district’s implementation of technology beginning in the 1995-1996 school year. The fundamental question that this scenario raises is, What is the balance between education, technology, and the budget? School leaders are currently facing or will face the dilemma of providing appropriate technology in times of shrinking budgets and staff.
The Bayou High School Blues
Authors: Stader David L.
Published: August 2006

This case study challenges aspiring school leaders to analyze data and develop school improvement objectives, strategies for sharing data, and strategies for change. Candidates must analyze the data, determine potential issues that should be addressed by the new principal, and develop a list of further data sources needed. Candidates could also select one area of concern and develop a research-based plan to address the concern. The case may be used in a campus or district leadership course, as a problem-based learning assignment, or as a way to demonstrate and apply the use of data to leadership decisions.
ABCG2 expression, function, and promoter methylation in human multiple myeloma
Authors: Turner Joel G. , Gump Jana L. , Zhang Chunchun , Cook James M. , Marchion Douglas , Hazlehurst Lori , Munster Pamela , Schell Michael J. , Dalton William S. , Sullivan Daniel M.
Published: August 2006

We investigated the role of the breast cancer resistance protein (BCRP/ABCG2) in drug resistance in multiple myeloma (MM). Human MM cell lines, and MM patient plasma cells isolated from bone marrow, were evaluated for ABCG2 mRNA expression by quantitative polymerase chain reaction (PCR) and ABCG2 protein, by Western blot analysis, immunofluorescence microscopy, and flow cytometry. ABCG2 function was determined by measuring topotecan and doxorubicin efflux using flow cytometry, in the presence and absence of the specific ABCG2 inhibitor, tryprostatin A. The methylation of the ABCG2 promoter was determined using bisulfite sequencing. We found that ABCG2 expression in myeloma cell lines increased after exposure to topotecan and doxorubicin, and was greater in logphase cells when compared with quiescent cells. Myeloma patients treated with topotecan had an increase in ABCG2 mRNA and protein expression after treatment with topotecan, and at relapse. Expression of ABCG2 is regulated, at least in part, by promoter methylation both in cell lines and in patient plasma cells. Demethylation of the promoter increased ABCG2 mRNA and protein expression. These findings suggest that ABCG2 is expressed and functional in human myeloma cells, regulated by promoter methylation, affected by cell density, up-regulated in response to chemotherapy, and may contribute to intrinsic drug resistance.
Smad7 promotes self-renewal of hematopoietic stem cells
Authors: Blank Ulrika , Karlsson Goran , Moody Jennifer L. , Utsugisawa Taiju , Magnusson Mattias , Singbrant Sofie , Larsson Jonas , Karlsson Stefan
Published: August 2006

The Smad-signaling pathway downstream of the transforming growth factor–β superfamily of ligands is an evolutionarily conserved signaling circuitry with critical functions in a wide variety of biologic processes. To investigate the role of this pathway in the regulation of hematopoietic stem cells (HSCs), we have blocked Smad signaling by retroviral gene transfer of the inhibitory Smad7 to murine HSCs. We report here that the self-renewal capacity of HSCs is promoted in vivo upon blocking of the entire Smad pathway, as shown by both primary and secondary bone marrow (BM) transplantations. Importantly, HSCs overexpressing Smad7 have an unperturbed differentiation capacity as evidenced by normal contribution to both lymphoid and myeloid cell lineages, suggesting that the Smad pathway regulates self-renewal independently of differentiation. Moreover, phosphorylation of Smads was inhibited in response to ligand stimulation in BM cells, thus verifying impairment of the Smad-signaling cascade in Smad7-overexpressing cells. Taken together, these data reveal an important and previously unappreciated role for the Smad-signaling pathway in the regulation of self-renewal of HSCs in vivo.
HBZ, a new important player in the mystery of adult T-cell leukemia
Authors: Mesnard Jean-Michel , Barbeau Benoît , Devaux Christian
Published: August 2006

Adult T-cell leukemia (ATL) was first described in 1977. A link between ATL and human T-cell leukemia virus type 1 (HTLV-1) was clearly established in the early 1980s. Over the years, many aspects of HTLV-1–induced cellular dysfunctions have been clarified. However, the detailed mechanism behind ATL occurrence remains unsolved. Presently, we are still unable to explain the absence of viral Tax protein (thought to play a central role in T-cell transformation) in more than 50% of ATL cells. A novel HTLV-1 HBZ protein, encoded on the negative strand, was characterized by our group and is currently the subject of intensive research efforts to determine its function in viral replication and/or pathophysiology. Recently, 4 studies reported on the existence of different HBZ isoforms and have investigated on their function in both ATL cells or animal models. One report suggests that the HBZ gene might have a bimodal function (at the mRNA and protein levels), which could represent an uncharacterized strategy to regulate viral replication and proliferation of infected T cells.
Optimizing immunotherapy in multiple myeloma: restoring the function of patients' monocyte-derived dendritic cells by inhibiting p38 or activating MEK/ERK MAPK and neutralizing interleukin-6 in progenitor cells
Authors: Wang Siqing , Hong Sungyoul , Yang Jing , Qian Jianfei , Zhang Xiang , Shpall Elizabeth , Kwak Larry W. , Yi Qing
Published: August 2006

Previous studies demonstrated that circulating dendritic cells (DCs) in myeloma patients were functionally abnormal. However, the phenotype and function of patients' monocyte-derived DCs (MoDCs), which are commonly used for immunotherapy, were poorly defined. This study was undertaken to examine the quality of MoDCs from myeloma patients compared with cells from healthy donors. We found that patient-derived MoDCs are phenotypically and functionally defective. Compared with their normal counterparts, patient-derived, mature MoDCs expressed significantly lower levels of CD1a, CD40, CD80, and HLA-DR and were poor at activating alloreactive T cells, presenting recall antigen, and activating autologous antigen- and myeloma-specific T cells. These abnormalities may be attributed to elevated production of autocrine cytokines such as IL-6, activated p38 and STAT3, and inhibited MEK/ERK signaling pathways in the progenitor cells. Treatment with neutralizing IL-6–specific antibody and, more importantly, p38 inhibitor, or both, could correct these abnormalities. Treating patient-derived cells with these agents not only significantly increased cell yield but also produced MoDCs that were as functional as their normal counterparts. Thus, this study has delineated the mechanistic defects of MoDCs from myeloma patients and identified ways for restoring the function of the cells to improve the efficacy of DC-based immunotherapy in this disease.
CD157 plays a pivotal role in neutrophil transendothelial migration
Authors: Ortolan Erika , Tibaldi Elena V. , Ferranti Bruna , Lavagno Luisa , Garbarino Giovanni , Notaro Rosario , Luzzatto Lucio , Malavasi Fabio , Funaro Ada
Published: August 2006

Paracellular diapedesis, a key step in leukocyte recruitment to the site of inflammation, occurs at endothelial junctions and is regulated by highly coordinated interactions between leukocytes and endothelium. We found that CD157, a glycosylphosphatidylinositol-anchored ectoenzyme belonging to the NADase/ADP-ribosyl cyclase family, plays a crucial role for neutrophil diapedesis, because its ligation with specific monoclonal antibodies (both on neutrophils or endothelial cells) results in altered neutrophil movement on the apical surface of endothelium and, ultimately, in loss of diapedesis. Real-time microscopy revealed that CD157 behaves as a sort of compass during the interaction between neutrophils and endothelial cells; indeed, following CD157 ligation, neutrophils appear disoriented, meandering toward junctions where they eventually stop without transmigrating. These findings are relevant in vivo because CD157-deficient neutrophils obtained from patients with paroxysmal nocturnal hemoglobinuria are characterized by a severely impaired diapedesis.
Hodgkin lymphoma and immunodeficiency in persons with HIV/AIDS
Authors: Biggar Robert J. , Jaffe Elaine S. , Goedert James J. , Chaturvedi Anil , Pfeiffer Ruth , Engels Eric A. ,   for the HIV/AIDS Cancer Match Study
Published: August 2006

In persons with HIV/AIDS (PWHAs), Hodgkin lymphoma (HL) risk is increased. However, HL incidence in PWHAs has unexpectedly increased since highly active antiretroviral therapy (HAART) was introduced. We linked nationwide HIV/AIDS and cancer registry data from 1980 through 2002. Immunity was assessed by CD4 T-lymphocyte counts at AIDS onset. Annual HL incidence rates were calculated for 4 through 27 months after AIDS onset. During 477 368 person years (py's) of follow-up in 317 428 persons with AIDS (PWAs), 173 HL cases occurred (36.2 per 105 py's). Incidence was significantly higher in 1996 to 2002 than earlier. Incidence in PWAs with 150 to 199 CD4 cells/μL was 53.7 per 105 py's, whereas in PWAs with fewer than 50 CD4 cells/μL, it was 20.7 per 105 py's (Ptrend = .002). For each HL subtype, incidence decreased with declining CD4 counts, but nodular sclerosing decreased more precipitously than mixed cellularity, thereby increasing the proportion of mixed cellularity HL seen in PWAs. We conclude that HL incidence is lower with severe immunosuppression than with moderate immunosuppression, and HAART-related improvements in CD4 counts likely explain the increasing HL incidence in PWHAS observed since 1996. With more severe immunosuppression, nodular sclerosing HL becomes infrequent, explaining the higher proportion of mixed cellularity HL found in PWAs. Pathogenesis implications are discussed.
Body mass index does not influence pharmacokinetics or outcome of treatment in children with acute lymphoblastic leukemia
Authors: Hijiya Nobuko , Panetta John C. , Zhou Yinmei , Kyzer Emily P. , Howard Scott C. , Jeha Sima , Razzouk Bassem I. , Ribeiro Raul C. , Rubnitz Jeffrey E. , Hudson Melissa M. , Sandlund John T. , Pui Ching-Hon , Relling Mary V.
Published: August 2006

There is conflicting information about the influence of body mass index (BMI) on the pharmacokinetics, toxicity, and outcome of chemotherapy. We compared pharmacokinetics, outcome, and toxicity data across 4 BMI groups (underweight, BMI ≤ 10th percentile; normal; at risk of overweight, BMI ≥ 85th and < 95th percentile; overweight, BMI ≥ 95th percentile) in 621 children with acute lymphoblastic leukemia (ALL) treated on 4 consecutive St Jude Total Therapy studies. Chemotherapy doses were not adjusted to ideal BMI. Estimates of overall survival (86.1% ± 3.4%, 86.0% ± 1.7%, 85.9% ± 4.3%, and 78.2% ± 5.5%, respectively; P = .533), event-free survival (76.2% ± 4.2%, 78.7% ± 2.1%, 73.4% ± 5.5%, and 72.7% ± 5.9%, respectively; P = .722), and cumulative incidence of relapse (16.0% ± 3.7%, 14.4% ± 1.8%, 20.6% ± 5.1%, and 16.7% ± 5.1%, respectively; P = .862) did not differ across the 4 groups. In addition, the intracellular levels of thioguanine nucleotides and methotrexate polyglutamates did not differ between the 4 BMI groups (P = .73 and P = .74, respectively). The 4 groups also did not differ in the overall incidence of grade 3 or 4 toxicity during the induction or postinduction periods. Further, the systemic clearance of methotrexate, teniposide, etoposide, and cytarabine did not differ with BMI (P > .3). We conclude that BMI does not affect the outcome or toxicity of chemotherapy in this patient population with ALL.
Multiple myeloma bone disease: pathophysiology of osteoblast inhibition
Authors: Giuliani Nicola , Rizzoli Vittorio , Roodman G. David
Published: August 2006

Multiple myeloma (MM) is a plasma cell malignancy characterized by a high capacity to induce osteolytic bone lesions. Bone destruction in MM results from increased osteoclast formation and activity that occur in close proximity to myeloma cells. However, histomorphometric studies have demonstrated that MM patients with osteolytic bone lesions have lower numbers of osteoblasts and decreased bone formation. This impaired bone formation plays a critical role in the bone-destructive process. Recently, the biologic mechanisms involved in the osteoblast inhibition induced by MM cells have begun to be elucidated. In this article, the pathophysiology underlying osteoblast inhibition in MM is reviewed.
Only the CD45RA+ subpopulation of CD4+CD25high T cells gives rise to homogeneous regulatory T-cell lines upon in vitro expansion
Authors: Hoffmann Petra , Eder Ruediger , Boeld Tina J. , Doser Kristina , Piseshka Biserka , Andreesen Reinhard , Edinger Matthias
Published: August 2006

Thymus-derived CD4+CD25+ regulatory T cells suppress autoreactive CD4+ and CD8+ T cells and thereby protect from autoimmunity. In animal models, adoptive transfer of CD4+CD25+ regulatory T cells has been shown to prevent and even cure autoimmune diseases as well as pathogenic alloresponses after solid organ and stem-cell transplantations. We recently described methods for the efficient in vitro expansion of human regulatory T cells for clinical applications. We now demonstrate that only CCR7- and L-selectin (CD62L)–coexpressing cells within expanded CD4+CD25high T cells maintain phenotypic and functional characteristics of regulatory T cells. Further analysis revealed that these cells originate from CD45RA+ naive cells within the CD4+CD25high T-cell compartment, as only this subpopulation homogeneously expressed CD62L, CCR7, cytotoxic T lymphocyte–associated antigen-4 (CTLA-4), and forkhead box P3 (FOXP3), produced no inflammatory cytokines and maintained robust suppressive activity after expansion. In contrast, cell lines derived from CD45RA– memory-type CD4+CD25high T cells lost expression of lymph node homing receptors CCR7 and CD62L, contained interleukin-2 (IL-2) and interferon-γ (IFN-γ) as well as IL-10–secreting cells, showed only moderate suppression and, most importantly, did not maintain FOXP3 expression. Based on these unexpected findings, we suggest that isolation and expansion of CD45RA+ naive CD4+ CD25high T cells is the best strategy for adoptive regulatory T (Treg)–cell therapies.
Hierarchical modularity of nested bow-ties in metabolic networks
Authors: Zhao Jing , Yu Hong , Luo Jian-Hua , Cao Zhi-Wei , Li Yi-Xue
Published: August 2006

Background

The exploration of the structural topology and the organizing principles of genome-based large-scale metabolic networks is essential for studying possible relations between structure and functionality of metabolic networks. Topological analysis of graph models has often been applied to study the structural characteristics of complex metabolic networks.

Results

In this work, metabolic networks of 75 organisms were investigated from a topological point of view. Network decomposition of three microbes (Escherichia coli, Aeropyrum pernix and Saccharomyces cerevisiae) shows that almost all of the sub-networks exhibit a highly modularized bow-tie topological pattern similar to that of the global metabolic networks. Moreover, these small bow-ties are hierarchically nested into larger ones and collectively integrated into a large metabolic network, and important features of this modularity are not observed in the random shuffled network. In addition, such a bow-tie pattern appears to be present in certain chemically isolated functional modules and spatially separated modules including carbohydrate metabolism, cytosol and mitochondrion respectively.

Conclusion

The highly modularized bow-tie pattern is present at different levels and scales, and in different chemical and spatial modules of metabolic networks, which is likely the result of the evolutionary process rather than a random accident. Identification and analysis of such a pattern is helpful for understanding the design principles and facilitate the modelling of metabolic networks.
P elements and MITE relatives in the whole genome sequence of Anopheles gambiae
Authors: Quesneville Hadi , Nouaud Danielle , Anxolabéhère Dominique
Published: August 2006

Background

Miniature Inverted-repeat Terminal Elements (MITEs), which are particular class-II transposable elements (TEs), play an important role in genome evolution, because they have very high copy numbers and display recurrent bursts of transposition. The 5' and 3' subterminal regions of a given MITE family often show a high sequence similarity with the corresponding regions of an autonomous Class-II TE family. However, the sustained presence over a prolonged evolutionary time of MITEs and TE master copies able to promote their mobility has been rarely reported within the same genome, and this raises fascinating evolutionary questions.

Results

We report here the presence of P transposable elements with related MITE families in the Anopheles gambiae genome. Using a TE annotation pipeline we have identified and analyzed all the P sequences in the sequenced A. gambiae PEST strain genome. More than 0.49% of the genome consists of P elements and derivates. P elements can be divided into 9 different subfamilies, separated by more than 30% of nucleotide divergence. Seven of them present full length copies. Ten MITE families are associated with 6 out of the 9 P subfamilies. Comparing their intra-element nucleotide diversities and their structures allows us to propose the putative dynamics of their emergence. In particular, one MITE family which has a hybrid structure, with ends each of which is related to a different P-subfamily, suggests a new mechanism for their emergence and their mobility.

Conclusion

This work contributes to a greater understanding of the relationship between full-length class-II TEs and MITEs, in this case P elements and their derivatives in the genome of A. gambiae. Moreover, it provides the most comprehensive catalogue to date of P- like transposons in this genome and provides convincing yet indirect evidence that some of the subfamilies have been recently active.
Activity and expression of urokinase-type plasminogen activator and matrix metalloproteinases in human colorectal cancer
Authors: Kim Tae-Dong , Song Kyoung-Sub , Li Ge , Choi Hoon , Park Hae-Duck , Lim Kyu , Hwang Byung-Doo , Yoon Wan-Hee
Published: August 2006

Background

Matrix metalloproteinase-2 (MMP-2), matrix metalloproteinase-9 (MMP-9), and urokinase-type plasminogen activator (uPA) are involved in colorectal cancer invasion and metastasis. There is still debate whether the activity of MMP-2 and MMP-9 differs between tumors located in the colon and rectum. We designed this study to determine any differences in the expression of MMP-2, MMP-9 and uPA system between colon and rectal cancer tissues.

Methods

Cancer tissue samples were obtained from colon carcinoma (n = 12) and rectal carcinomas (n = 10). MMP-2 and MMP-9 levels were examined using gelatin zymography and Western blotting; their endogenous inhibitors, tissue inhibitor of metalloproteinase-2 (TIMP-2) and tissue inhibitor of metalloproteinase-1 (TIMP-1), were assessed by Western blotting. uPA, uPAR and PAI-1 were examined using enzyme-linked immunosorbent assay (ELISA). The activity of uPA was assessed by casein-plasminogen zymography.

Results

In both colon and rectal tumors, MMP-2, MMP-9 and TIMP-1 protein levels were higher than in corresponding paired normal mucosa, while TIMP-2 level in tumors was significantly lower than in normal mucosa. The enzyme activities or protein levels of MMP-2, MMP-9 and their endogenous inhibitors did not reach a statistically significant difference between colon and rectal cancer compared with their normal mucosa. In rectal tumors, there was an increased activity of uPA compared with the activity in colon tumors (P = 0.0266), however urokinase-type plasminogen activator receptor (uPAR) and plasminogen activator inhibitor-1 (PAI-1) showed no significant difference between colon and rectal cancer tissues.

Conclusion

These findings suggest that uPA may be expressed differentially in colon and rectal cancers, however, the activities or protein levels of MMP-2, MMP-9, TIMP-1, TIMP-2, PAI-1 and uPAR are not affected by tumor location in the colon or the rectum.
Patient expectations of fair complaint handling in hospitals: empirical data
Authors: Friele Roland D , Sluijs Emmy M
Published: August 2006

Background

A common finding in several studies is patients' dissatisfaction with complaint handling in health care. The reasons why are for the greater part unknown. The key to an answer may be found in a better understanding of patients' expectations. We investigated patients' expectations of complaint handling in hospitals.

Methods

Subjects were patients who had lodged a complaint at the complaint committees of 74 hospitals in the Netherlands. A total of 424 patients (response 75%) completed a written questionnaire at the start of the complaint procedures. Derived from justice theory, we asked what they expected from fair procedures, fair communication and fair outcome of complaint handling.

Results

The predominant reason for complainants to lodge a complaint was to prevent the incident from happening again. Complainants expected fair procedures from the complaint committee, in particular an impartial position. This was most important to 87% of the complainants. They also expected to be treated respectfully. Furthermore, they expected the hospital and the professional involved to respond to their complaint. A change in hospital performances was the most wanted outcome of complaint handling, according to 79% of the complainants. They also expected disclosure from the professionals. Professionals should admit a mistake when it had occurred. More complainants (65%) considered it most important to get an explanation than an apology (41%). Only 32% of complainants expected the professional to make an effort to restore the doctor-patient relationship. A minority of complainants (7%) wanted financial compensation.

Conclusion

Nearly all complainants want to prevent the incident from happening again, not out of pure altruism, but in order to restore their sense of justice. We conclude that complaint handling that does not allow for change is unlikely to meet patients' expectations. Secondly, complaint handling should not be left exclusively to complaint committees, the responses of hospital and professionals are indispensable.
A system for studying evolution of life-like virtual organisms
Authors: Neyfakh Alex A , Baranova Natalya N , Mizrokhi Lev J
Published: August 2006

Background

Fitness landscapes, the dependences of fitness on the genotype, are of critical importance for the evolution of living beings. Unfortunately, fitness landscapes that are relevant to the evolution of complex biological functions are very poorly known. As a result, the existing theory of evolution is mostly based on postulated fitness landscapes, which diminishes its usefulness. Attempts to deduce fitness landscapes from models of actual biological processes led, so far, to only limited success.

Results

We present a model system for studying the evolution of biological function, which makes it possible to attribute fitness to genotypes in a natural way. The system mimics a very simple cell and takes into account the basic properties of gene regulation and enzyme kinetics. A virtual cell contains only two small molecules, an organic nutrient A and an energy carrier X, and proteins of five types – two transcription factors, two enzymes, and a membrane transporter. The metabolism of the cell consists of importing A from the environment and utilizing it in order to produce X and an unspecified end product. The genome may carry an arbitrary number of genes, each one encoding a protein of one of the five types. Both major mutations that affect whole genes and minor mutations that affect individual characteristics of genes are possible. Fitness is determined by the ability of the cell to maintain homeostasis when its environment changes. The system has been implemented as a computer program, and several numerical experiments have been performed on it. Evolution of the virtual cells usually involves a rapid initial increase of fitness, which eventually slows down, until a fitness plateau is reached. The origin of a wide variety of genetic networks is routinely observed in independent experiments performed under the same conditions. These networks can have different, including very high, levels of complexity and often include large numbers of non-essential genes.

Conclusion

The described system displays a rich repertoire of biologically sensible behaviors and, thus, can be useful for investigating a number of unresolved issues in evolutionary biology, including evolution of complexity, modularity and redundancy, as well as for studying the general properties of genotype-to-fitness maps.

Reviewers

This article was reviewed by Drs. Eugene Koonin, Shamil Sunyaev and Arcady Mushegian.
Metalloproteinase and inhibitor expression profiling of resorbing cartilage reveals pro-collagenase activation as a critical step for collagenolysis
Authors: Milner Jennifer M , Rowan Andrew D , Cawston Tim E , Young David A
Published: August 2006

Excess proteolysis of the extracellular matrix (ECM) of articular cartilage is a key characteristic of arthritis. The main enzymes involved belong to the metalloproteinase family, specifically the matrix metalloproteinases (MMPs) and a group of proteinases with a disintegrin and metalloproteinase domain with thrombospondin motifs (ADAMTS). Chondrocytes are the only cell type embedded in the cartilage ECM, and cell-matrix interactions can influence gene expression and cell behaviour. Thus, although the use of monolayer cultures can be informative, it is essential to study chondrocytes encapsulated within their native environment, cartilage, to fully assess cellular responses. The aim of this study was to profile the temporal gene expression of metalloproteinases and their endogenous inhibitors, the tissue inhibitors of metalloproteinases (TIMPs), reversion-inducing cysteine-rich protein with Kazal motifs (RECK), and α2-macroglobulin (α2M), in actively resorbing cartilage. The addition of the pro-inflammatory cytokine combination of interleukin-1 (IL-1) + oncostatin M (OSM) to bovine nasal cartilage induces the synthesis and subsequent activation of pro-metalloproteinases, leading to cartilage resorption. We show that IL-1+OSM upregulated the expression of MMP-1, -2, -3, -9, 12, -13, -14, TIMP-1, and ADAMTS-4, -5, and -9. Differences in basal expression and the magnitude of induction were observed, whilst there was no significant modulation of TIMP-2, -3, RECK, or ADAMTS-15 gene expression. IL-1+OSM downregulated MMP-16,TIMP-4, and α2M expression. All IL-1+OSM-induced metalloproteinases showed marked upregulation early in the culture period, whilst inhibitor expression was reduced throughout the stimulation period such that metalloproteinase production would be in excess of inhibitors. Moreover, although pro-collagenases were upregulated and synthesized early (by day 5), collagenolysis became apparent later with the presence of active collagenases (day 10) when inhibitor levels were low. These findings indicate that the activation cascades for pro-collagenases are delayed relative to collagenase expression, further confirm the coordinated regulation of metalloproteinases in actively resorbing cartilage, and support the use of bovine nasal cartilage as a model system to study the mechanisms that promote cartilage degradation.
Comparison of gene expression profiles in core biopsies and corresponding surgical breast cancer samples
Authors: Zanetti-Dällenbach Rosanna , Vuaroqueaux Vincent , Wight Edward , Labuhn Martin , Singer Gad , Urban Patrick , Eppenberger Urs , Holzgreve Wolfgang , Eppenberger-Castori Serenella
Published: August 2006

Introduction

Gene expression profiling has been successfully used to classify breast cancer into clinically distinct subtypes, and to predict the risk of recurrence and treatment response. The aim of this study was to investigate whether the gene expression profile (GEP) detected in a core biopsy (CB) is representative for the entire tumor, since CB is an important tool in breast cancer diagnosis. Moreover, we investigated whether performing CBs prior to the surgical excision could influence the GEP of the respective tumor.

Methods

We quantified the RNA expression of 60 relevant genes by quantitative real-time PCR in paired CBs and surgical specimens from 22 untreated primary breast cancer patients. Subsequently, expression data were compared with independent GEPs obtained from tumors of 317 patients without preceding CB.

Results

In 82% of the cases the GEP detected in the CB correlated very well with the corresponding profile in the surgical sample (rs ≥ 0.95, p < 0.001). Gene-by-gene analysis revealed four genes significantly elevated in the surgical sample compared to the CB; these comprised genes mainly involved in inflammation and the wound repair process as well as in tumor invasion and metastasis.

Conclusion

A GEP detected in a CB are representative for the entire tumor and is, therefore, of clinical relevance. The observed alterations of individual genes after performance of CB deserve attention since they might impact the clinical interpretation with respect to prognosis and therapy prediction of the GEP as detected in the surgical specimen following CB performance.