bluuebunny/crossref_metadata_2025 huggingface dataset:
Growth arrest-specific gene 6 (GAS6)
Authors: Fernández-Fernández Laura , Bellido-Martín Lola , García de Frutos Pablo
Published: September 2008

GAS6 (growth arrest-specific 6) belongs structurally to the family of plasma vitamin K-dependent proteins. GAS6 has a high structural homology with the natural anticoagulant protein S, sharing the same modular composition and having 40% sequence identity. Despite this, the low concentration of GAS6 in plasma and the pattern of tissue expression of GAS6 suggest a distinct function among vitamin-K dependent proteins. Indeed, GAS6 has growth factor-like properties through its interaction with receptor tyrosine kinases of the TAM family; Tyro3, Axl and MerTK. GAS6 employs a unique mechanism of action, interacting through its vitamin K-dependent GLA (γ-carboxyglutamic acid) module with phosphatidylserine-containing membranes and through its carboxy-terminal LamG domains with the TAM membrane receptors. During the last years there has been a considerable expansion of our knowledge of the biology of TAM receptors that has lead to a clear picture of their importance in inflammation, haemostasis and cancer, making this system an interesting target in biomedicine. The innate immune response and the coagulation cascade have been shown to be interconnected. Mediators of inflammation are essential in the initiation and propagation of the coagulation cascade, while natural anticoagulants have important anti-inflammatory functions. GAS6 represents a new player in this context, while protein S seems to have new functions beyond its anticoagulant role through its interaction with TAM receptors.
Factor IX: Insights from knock-out and genetically engineered mice
Authors: Monahan Paul E.
Published: September 2008

The study of coagulation factors has been rapidly advanced by studies performed in genetically engineered mouse strains. Investigation of factor IX (FIX) has benefited from excellent genedeleted mouse models that recapitulate many of the features of human haemophilia B. Moreover, advanced positional cloning techniques and availability of technology to allow not only knock-out mice, but also knock-in and knock-down mice, provide new opportunities to observe genotype-phenotype and structure-function correlations regarding FIX, as well as the interaction of FIX with inflammatory, immune, and tissue repair systems. In this paper, available FIX knock-out mice and additional haemophilia B mouse models are reviewed specifically in regards to observations these models have facilitated concerning: factor IX gene expression and factor IX protein pharmacokinetics; the role of FIX in haemostasis, thrombosis and wound healing; insights into coagulation FIX arising out of gene therapy applications in haemophilia mouse models; immunology of tolerance or loss of tolerance of FIX and inhibitor antibody formation.
Risk factors of vitamin K antagonist overcoagulation
Authors: Cadiou Gwenaëlle , Varin Rémi , Levesque Hervé , Grassi Vanessa , Benichou Jacques , Tiret Isabelle , Dieu Bernard , Lecam-Duchez Véronique , Borg Jeanne-Yvonne , Muller Jean-Michel , Benhamou Ygal , Marie Isabelle
Published: September 2008

The aims of this case-control study were to identify in vitamin K antagonist (VKA)-treated unselected patients, factors associated with international normalised ratio (INR) values: (i) greater than 6.0.;and (ii) ranging from 4.0 to 6.0 complicated with bleeding. We also assessed VKA-related morbidity in these patients. During a two-month period, 4,188 consecutive and unselected patients were referred to our Emergency Department. At admission, the medical records of each patient and two age- and sex-matched controls were reviewed for: both duration and indication of VKA therapy, previous medical history of VKA-related haemorrhage, underlying co-morbidities, concomitant medications other than VKA, duration of hospitalization and deaths’ causes. Of these 4,188 subjects,50 case-patients (1.19%) were identified; both case-patients and controls did not differ as regards indications and patterns of VKA therapy. Interestingly, two-thirds of case-patients were women, suggesting that female gender may be a risk factor of VKA over-coagulation onset. We identified the following risk factors of VKA over-coagulation: previous medical history of INR levels over therapeutic range, therapy with antibiotics, amiodarone and proton pump inhibitors, as well as fever. A total of 88% of case-patients were hospitalized; mean duration of patients’ hospitalization was seven days [range:1–56 days];no patient died from major bleeding. Our study underscores that it is of utmost importance to consider the strength of indication before starting VKA therapy, as this therapy has been responsible for as high as 1.19% of admissions in unselected subjects referred to an Emergency Department. Our data therefore suggest that internists should be aware of VKA-related high morbidity, particularly in situations at risk of VKA over-coagulation.
Greater reduction of platelet activation markers and platelet-monocyte aggregates by prasugrel compared to clopidogrel in stable coronary artery disease
Authors: arenhorst Christoph , James Stefan , Brandt John T. , Jakubowski Joseph A. , Winters Kenneth J. , Wallentin Lars , Erlinge David , Braun Oscar Ö. , Johnell Matilda , Siegbahn Agneta
Published: September 2008

Prasugrel, a novel P2Y12 ADP-receptor antagonist, has been reported to achieve greater inhibition of platelet aggregation compared to clopidogrel as assessed by light transmission aggregometry. It was the objective of this study to investigate the effect of prasugrel on alternative markers of platelet activation in comparison to a high loading dose and the approved maintenance dose of clopidogrel. One hundred ten aspirintreated patients with stable coronary artery disease were randomized to a loading dose (LD, day 1)/ maintenance dose (MD, days 2–29) of prasugrel 60 mg/10 mg or clopidogrel 600 mg/75 mg. Platelet activation markers were analyzed by whole blood flow cytometry pre-dose and at 2 and 24 hours after LD and pre-dose at 14 and 29 days. After stimulation with 20 µM ADP, 2 hours after LD, significantly lower expression of activated GPIIb/IIIa (4.3 vs. 21.8 [mean fluorescent intensity (MFI)], p < 0.001) and P-selectin (2.0 vs. 11.7 MFI, p < 0.001) along with decreased formation of platelet-monocyte aggregates (16.4% vs.29.6% positive cells, p < 0.001) was observed with prasugrel versus clopidogrel. All these effects were maintained through 24 hours and during the MD period. In conclusion, prasugrel 60 mg LD and 10 mg MD inhibit several markers of platelet activation and the formation of platelet-monocyte aggregates more effectively than a 600 mg LD and 75 mg MD of clopidogrel. Attenuated platelet aggregation and reduced expression of platelet procoagulant and pro-inflammatory markers with prasugrel suggest the potential to reduce cardiovascular events both in the acute setting and in longterm treatment.
Maintained effectiveness of an electronic alert system to prevent venous thromboembolism among hospitalized patients
Authors: Lecumberri Ramón , Marqués Margarita , Díaz-Navarlaz María , Panizo Elena , Toledo Jon , García-Mouriz Alberto , Páramo José A.
Published: September 2008

Despite current guidelines, venous thromboembolism (VTE) prophylaxis is underused. Computerized programs to encourage physicians to apply thromboprophylaxis have been shown to be effective in selected populations. Our aim was to analyze the impact of the implementation of a computer- alert system for VTE risk in all hospitalized patients of a teaching hospital. A computer program linked to the clinical record database was developed to assess all hospitalized patients’VTE risk daily. The physician responsible for patients at high risk was alerted, but remained free to order or withhold prophylaxis. Over 19,000 hospitalized, medical and surgical, adult patients between January to June 2005 (pre-intervention phase), January to June 2006 and January to June 2007 (postintervention phase), were included. During the first semesters of 2006 and 2007, an electronic alert was sent to 32.8% and 32.2% of all hospitalized patients, respectively. Appropriate prophylaxis among alerted patients was ordered in 89.7% (2006) and 88.5% (2007) of surgical patients, and in 49.2% (2006) and 64.4% (2007) of medical patients. A sustained reduction of VTE during hospitalization was achieved, Odds ratio (OR): 0.53, 95% confidence interval (CI) (0.25–1.10) and OR: 0.51, 95%CI (0.24–1.05) during the first semesters of 2006 and 2007 respectively, the impact being significant (p<0.05) among medical patients in 2007, OR: 0.36, 95%CI (0.12–0.98). The implementation of a computer- alert program helps physicians to assess each patient’s thrombotic risk, leading to a better use of thromboprophylaxis, and a reduction in the incidence of VTE among hospitalized patients. For the first time, an intervention aimed to improveVTE prophylaxis shows maintained effectiveness over time.
Analysis of the venous thromboembolic risk associated with severe postpartum haemorrhage in the NOHA First cohort
Authors: Chauleur Céline , Cochery-Nouvellon Eva , Mercier Eric , Aya Guy , Marès Pierre , Mismetti Patrick , Lissalde-Lavigne Géraldine , Gris Jean-Christophe
Published: September 2008

Severe postpartum haemorrhages (PPH) are responsible for maternal morbidity/mortality. Their complex management sometimes requires haemostatic supplementation, and therapeutic trials on fibrinogen or activated factor VII, which may add to the thrombotic risk, are currently being considered. Furthermore, there is a risk of venous thromboembolism (VTE) during the postpartum period, hence we studied the relationship between severe PPH and VTE in women during their first pregnancy. Among the 32,463 women enrolled between January 1, 1999 and February 1, 2004 in the NOHA First cohort, 317 developed severe PPH, 11 postpartum VTE and 60 had postpartum superficial vein thrombosis (SVT). In the women with severe PPH, whilst there were no episodes of VTE, there were three episodes of SVT, which occurred 6 weeks postpartum. All of the women with severe PPH received packed red blood cell (RBC) units, 29 (9.1%) platelets units, 51 (16.1%) fresh frozen plasma and 29 (9.1%) fibrinogen concentrates. Three patients with both severe PPH and SVT received only packed RBC. Severe PPH or packed RBC unit transfusion were associated with postpartum SVT (adjusted relative risk: 5.3 (1.6–17) and 4.7 (1.5–15) respectively), independent of caesarean section delivery and low-molecular- weight heparin (LMWH) use in the postpartum, but were not independent indicators of one another. This the VTE and SVT risks associated with severe PPH are low (<1% and <2%, respectively).Severe PPH increases the risk of postpartum SVT, but transfusion with platelet units and plasma supplementation using fresh frozen plasma or fibrinogen concentrates do not markedly modulate the risk of venous thrombosis.
Factor VIIa and its potential therapeutic use in bleeding-associated pathologies
Authors: Hedner Ulla
Published: September 2008

Recombinant FVIIa (rFVIIa) was developed for treatment of haemophilia patients with inhibitors against FVIII/FIX. The haemostatic efficacy rate of 80–90% including major orthopaedic surgery (dosing of 90–120 µg/kg every other hour [h] for at least the first 24 h) was achieved in these patients. In a home-treatment setting the efficacy rate of haemostasis in mild-moderate bleedings was 92% (average number of 90 µg/kg doses was 2.2). A wide individual variation regarding recovery of rFVIIa (46 ± 12%; median 43%) as well as of clearance rate (36 ± 8 ml/kg/h; median 32 ml/kg/h in adults;children 2–3 times higher) has been observed. Thus children may require higher doses than adults. Accordingly the use of a dose of 270 µg/kg in one single injection was approved in the EU. Recent experience indicates that repeated doses of rFVIIa may decrease the number of bleeds in “target joints”, and thus may be useful as prophylaxis in severe hemophilia with inhibitors. Pharmacological concentrations of rFVIIa have been shown to enhance the thrombin generation on thrombin activated platelets in a cell-based model. By doing so a tight structured fibrin haemostatic plug resistant against premature lysis is formed. rFVIIa has been shown to induce haemostasis not only in haemophilia but also in other situations characterized by an impaired thrombin generation such as platelet defects, dilution coagulopathy developed as a result of trauma and extensive surgery. A special form of profuse bleeding, that may cause extensive problems is postpartum haemorrhage.
Phorbol 12-myristate 13-acetate (PMA) responsive sequence in Gαq promoter during megakaryocytic differentiation
Authors: Jalagadugula Gauthami , Dhanasekaran Danny N. , Rao A. Koneti
Published: September 2008

Gαq plays a major role in platelet signal transduction, but little is known regarding its transcriptional regulation. We have reported that Gαq is upregulated during phorbol 12-myristate 13-acetate (PMA)-induced megakaryocytic transformation of human erythroleukemia (HEL) cells and regulated by EGR-1, an early growth transcription factor. These studies focused on the initial 238 bp of the 5’ upstream region of the Gαq gene. In the present studies we characterize a minimal region -1042/-1037 bp from ATG in the 5’ upstream of the Gαq promoter that is associated with PMA responsiveness. In luciferase reporter gene studies in HEL cells, Gαq 5’ upstream promoter sequence -1042/-1 showed an about four-fold increased activity in PMA-treated compared to untreated cells. Deletion of 6-nt-1042/-1037 eliminated the difference. Gel-shift studies on Gαq probe (-1042/-1012 bp) revealed binding of EGR-1 with PMA-treated but not untreated nuclear extracts, and this was dependent on the sequence –1042/-1037.Silencing of endogenous EGR-1 inhibited Gαq induction by PMA. MEK/ERK inhibitor U0126 blocked PMA effect on promoter activity of the -1042/-1 construct. In conclusion, EGR-1 binding to sequence –1042/-1037 bp in Gαq promoter mediates the induction of Gαq gene by PMA via the MEK/ERK signaling pathway. These studies provide the first evidence of a PMA-responsive element in Gαq promoter, and new insights into regulation of Gαq gene by EGR-1.
Systems Approach to Understanding Electromechanical Activity in the Human Heart
Authors: Rudy Yoram , Ackerman Michael J. , Bers Donald M. , Clancy Colleen E. , Houser Steven R. , London Barry , McCulloch Andrew D. , Przywara Dennis A. , Rasmusson Randall L. , Solaro R. John , Trayanova Natalia A. , Van Wagoner David R. , Varró András , Weiss James N. , Lathrop David A.
Published: September 2008

The National Heart, Lung, and Blood Institute (NHLBI) convened a workshop of cardiologists, cardiac electrophysiologists, cell biophysicists, and computational modelers on August 20 and 21, 2007, in Washington, DC, to advise the NHLBI on new research directions needed to develop integrative approaches to elucidate human cardiac function. The workshop strove to identify limitations in the use of data from nonhuman animal species for elucidation of human electromechanical function/activity and to identify what specific information on ion channel kinetics, calcium handling, and dynamic changes in the intracellular/extracellular milieu is needed from human cardiac tissues to develop more robust computational models of human cardiac electromechanical activity. This article summarizes the workshop discussions and recommendations on the following topics: (1) limitations of animal models and differences from human electrophysiology, (2) modeling ion channel structure/function in the context of whole-cell electrophysiology, (3) excitation–contraction coupling and regulatory pathways, (4) whole-heart simulations of human electromechanical activity, and (5) what human data are currently needed and how to obtain them. The recommendations can be found on the NHLBI Web site at http://www.nhlbi.nih.gov/meetings/workshops/electro.htm.
Collective Dispute Resolution in the Public Sector: The Nordic Countries Compared
Authors: Stokke Torgeir Aarvaag , Seip Åsmund Arup
Published: September 2008

Collective bargaining in the public sector in the Nordic countries is conducted both at the central and the local level. Dispute resolution at the central level aims at avoiding open conflict, and takes the form of mediation. In addition, a variety of self-imposed or legal regulations address who is entitled to take part in industrial action and how the bargaining structure is designed. Legal intervention plays a role in two countries, while the other two adhere to a principle of self-regulation. When it comes to the protection of essential services, legal intervention has tendencies towards overprotection while self-regulation has sparked most discussion in the direction of underprotection. Still, there are signs of convergence. Dispute resolution at the local level aims at concluding a wage disagreement, and usually takes the form of arbitration. The arbitration rate is low, two to five percent per bargaining unit per year. A decentralization of bargaining would only solve the problem of protecting essential services if all groups benefited from decentralization. Since this is not likely, decentralization is likely to either remain partial or trigger recentralization. The problem of protecting essential services will therefore remain at the core of public sector bargaining.
Dispute Regulation in Essential Public Services in Italy: Strengths and Weaknesses of a `Pluralist Approach'
Authors: Bordogna Lorenzo
Published: September 2008

This article analyses the system of dispute regulation in essential public services in Italy as an example of the strengths and weaknesses of a pluralist approach to the issue under examination. That is, an approach which, in one of the few EU countries where the right to strike is constitutionally protected, assigns important regulatory responsibilities to the parties — trade unions and employers — under the supervision of a newly created authority, the Guarantee Commission. The article stresses how such an approach has proved on the whole to be rather effective, capable of reconciling the employees' right to strike with the citizens' rights equally protected by the constitution. However, discussing the case of a massive wildcat dispute in the local transport system, it also underlines how this approach is doomed to fail whenever a dissociation between the actors involved in the regulation and those promoting the conflict occurs. The article suggests that an effective system of dispute regulation in essential public services, especially if based on a pluralist approach, cannot operate in isolation but requires coherent rules in the labour relations system as a whole, namely regarding the collective bargaining procedures and even more the rules of the representation system.
Retrospect and Prospects for Collective Regulation in the Australian Public Service
Authors: O'Brien John , O'Donnell Michael
Published: September 2008

The article examines changes in the collective regulation of employment relations in the Australian Public Service over the last three decades. While federal Labor Governments in the 1990s briefly experimented with agency bargaining before returning to a service-wide approach to wage bargaining, the Howard Coalition Government encouraged federal public sector managers to individualize employment relations through the widespread offer of Australian Workplace Agreements and non-union collective agreements. This agenda was reinforced by policy parameters overseen by the Department of Employment and Workplace Relations, which placed constraints on the flexibility available to managers to negotiate agency-specific employment arrangements. Despite concerted efforts to marginalize the role of the Community and Public Sector Union since 1996, the union has maintained approximately 70 percent collective bargaining coverage within the Australian Public Service. Nevertheless, the 2005 amendments to the Workplace Relations Act (1996) imposed further restrictions on unions' right of entry to public sector workplaces, made the taking of industrial action more difficult, and sent a clear signal to the Government's managerial agents to adopt a more hostile approach to public sector unions. This hostile environment has brought to the fore issues of union organization and effectiveness and the concomitant need to maintain union democracy and an active voice for members in union decision-making processes.
Closing the Gap? The Role of Wage, Welfare and Industry Policy in Promoting Social Inclusion
Authors: Smyth Paul
Published: September 2008

Australia's social policy regime has been described as `social protection by other means' (SPM). Its foundation is attributed to the Harvester Judgment's minimum wage decision and is said to have persisted more or less successfully from 1907 to 2005 when the Howard Government passed industrial relations reforms known as the Work Choices legislation. This proposed that wage minima should be determined more by what the market can afford than previous welfare criteria. In 2008 the new Labor Government will need to revisit the role of the minimum wage in relation to social policy. Many see SPM as a failed model in the context of economic globalization and propose that Australia must reckon with creating a new European-style welfare state system of `flexicurity'. This article proposes that the perception of a crisis in SPM is fundamentally mistaken. Australian welfare has been far less reliant on wage determination than has been supposed and points towards a socially inclusive policy framework that is readily attainable.
Paid Annual Leave and Working Hours: Evidence from the HILDA Survey
Authors: Wooden Mark , Warren Diana
Published: September 2008

Using data from wave 5 of the Household, Income and Labour Dynamics in Australia (HILDA) Survey, this study examines: (1) the extent to which Australian employees use their annual leave entitlements; and (2) the association between annual leave taking and weekly hours of work. After restricting attention to employees likely to have entitlement to at least 4 weeks of paid annual leave, it is found that the mean number of days of leave taken per year is around 16 and that the majority of employees (63%) take less than 20. The incidence of annual leave taking is found to vary positively with the number of usual weekly hours of work, but the size of this effect is small and weak.
Awakening to Race
Authors: Turner Jack
Published: September 2008

Ralph Ellison offers crucial insight into the meaning of conscientious citizenship in American democracy. In doing so, he follows his nineteenth-century Transcendentalist forebears—Emerson, Thoreau, and Whitman—who have become key figures in contemporary efforts to theorize liberal democratic character. At the center of Emersonian ethics is the idea of “awakening.” “Awakening” is the Emersonians' name for honest and courageous confrontation with reality. Ellison broadens the Emersonians' vision by insisting that one cannot be “well awake” in America without confronting the ways historical white supremacy shapes one's identity and chances in life. Political theorists who draw inspiration from the Emersonians in theorizing democratic individuality need to pay attention to Ellison—for he demonstrates that one cannot achieve democratic individuality without awakening to race.
Discourses of Danger
Authors: Ferguson Kathy E.
Published: September 2008

Government, media, and medical accounts of Emma Goldman converged to create her public presence in the U.S. as a “dangerous individual.” The prevailing discourses constituted Goldman as violent, utilizing her alleged menace to distract attention from far more egregious violence against labor by state and corporate forces. Goldman responded by denying, confronting, and redirecting the alarmed gaze toward greater risks left underarticulated in hegemonic accounts. Goldman's bold confrontations with authorities constituted a kind of anarchist parrhesia, fearless speech, a relentless truth-telling practice that risked her own security in pursuit of her “beautiful ideal.” The labor of remembering America's history of class violence hones our attention to the complex discursive processes by which some historical facts come to count in prevailing narratives, while others fade into obscurity.
The Color of Memory
Authors: Booth W. James
Published: September 2008

In this article, I am concerned with the relationship between the visibility of race as color, the memory of injustice, and American identity. The visibility of color would seem to make it a daily reminder of race and its history, and in this way to be intimately a part of American memory and identity. Yet the tie between memory and color is anything but certain or transparent. Rather, as I shall argue, it is a latticework composed of things remembered, forgotten, glossed, or idealized, and the traces they leave in our world, traces that keep that past from falling into the oblivion of forgetfulness. Finally, color, memory, and identity together belong to the struggle over racial justice in this country, a battle in part to recognize the past, of which color is the visible reminder, and to fashion an American identity that does not seek to render it invisible. Ralph Ellison's writings on memory and race, and particularly his defining work, the Invisible Man, map these issues and some of the ways of approaching them. The present essay is an exploration of those issues, conducted through an engagement with his work.
Review Essay: Finnish Academic Publishing in Sociology
Authors: Antikainen Ari
Published: September 2008

This article analyses the current state and changes in academic sociological publishing in Finland. It describes the situation in different sectors of sociological publishing: in scientific journals, in academic publications and in the publications of the institutional and commercial sectors, especially in textbooks. The article discusses the strengths and weaknesses of each sector. The author is particularly concerned with the future of monographs in the Finnish results-based university system. Through a set of examples, the review paints a picture of the institutionalization, expansion and differentiation of Finnish sociology. Because Finland is a small language and market area, and a representative of the Nordic model, sociological production is dependent on state measures and support.
Nanotech's History
Authors: Shew Ashley
Published: September 2008

Nanotechnology is viewed by those in favor of its development in two different ways, and the divide is not recent. This article describes the origins of the differing visions of nanotechnology and examines their broader impacts. The typical history of the field tells nothing about these differing visions, which perhaps misleads. At least two distinct camps among scientists and engineers pursue work on the nanoscale, but they rarely interact, and when they do, they get nowhere. This article looks first at definitional issues in the field; then turns to the common history of nanotechnology, the history's shortcomings, and one particular episode that highlights the divide; and then examines the broader impacts of this dispute. The divide among those interested in nanotech tells something about the way different groups of people see technology and the application of science. This historical review clarifies controversy over societal issues and terminology in nanotechnology.
Spontaneous Abortion in a Danish Population-Based Cohort of Childhood Cancer Survivors
Authors: Winther Jeanette F. , Boice John D. , Svendsen Anne Louise , Frederiksen Kirsten , Stovall Marilyn , Olsen Jørgen H.
Published: September 2008

Purpose

Radiation induces germ-cell mutations in experimental animals that result in adverse pregnancy outcomes, as does uterine damage caused by high-dose radiotherapy. We assessed the risks for spontaneous abortion and stillbirths among cancer survivors who received radiotherapy and subsequently became pregnant.

Patients and Methods

We identified 1,688 female survivors of childhood cancer in the Danish Cancer Registry. Radiation doses to the ovary and uterus were characterized as high to low. The pregnancy outcomes of survivors, 2,737 sisters, and 16,700 comparison women in the population were identified from nationwide registries. The proportions of pregnancies among survivors that resulted in a livebirth, stillbirth, or abortion were compared with the equivalent proportions among the two comparison groups, and proportion ratios (PRs) were computed with sisters as referent.

Results

More than 34,000 pregnancies were evaluated, 1,479 of which were among cancer survivors. No significant differences were seen between survivors and comparison women in the proportions of livebirths, stillbirths, or all types of abortions combined. Survivors, however, had a 23% excess risk for spontaneous abortion (PR, 1.23; 95% CI, 1.0 to 1.5), related primarily to prior radiation treatments (PR, 1.58; 95% CI, 1.2 to 2.2) and especially high-dose radiotherapy to the ovaries and uterus (PR, 2.8; 95% CI, 1.7 to 4.7).

Conclusion

The pregnancy outcomes of survivors were similar to those of comparison women. A slight excess risk for spontaneous abortion may have resulted from uterine damage after high-dose pelvic radiotherapy, consistent with previous studies, although radiation-induced germinal mutations or decreased hypothalamic-pituitary-ovarian function could not be ruled out.
Ten-Year Follow-Up of 3 Years of Oral Adjuvant Clodronate Therapy Shows Significant Prevention of Osteoporosis in Early-Stage Breast Cancer
Authors: Saarto Tiina , Vehmanen Leena , Blomqvist Carl , Elomaa Inkeri
Published: September 2008

Purpose

We have previously reported that 3-year adjuvant clodronate treatment prevents bone loss in breast cancer patients. Here we report the 10-year follow-up data of clodronate in the prevention of treatment-related osteoporosis in women with early-stage breast cancer.

Patients and Methods

Two hundred sixty-eight pre- and postmenopausal, node-positive breast cancer patients were randomly assigned to clodronate, 1.6 g orally administered daily, or to control groups for 3 years. Premenopausal women were treated with adjuvant CMF chemotherapy; and postmenopausal women were treated with antiestrogens, either 20 mg tamoxifen or 60 mg toremifene, for 3 years. The bone mineral density (BMD) of the lumbar spine and hip was measured before treatment and at 1, 2, 3, 5, and 10 years after therapy.

Results

Eighty-nine disease-free patients were included in the analyses of osteoporosis-free survival. During the 10-year period, 24 of 89 patients were diagnosed with osteoporosis. Fourteen patients developed spinal osteoporosis (three of 41 in the clodronate group, and 11 of 48 in the control group), and 14 of 89 patients were diagnosed with hip osteoporosis (seven of 41 in the clodronate group, and seven of 48 in the control group). The 10-year spinal, osteoporosis-free survival rate was 92.7% in the clodronate group, and 77.0% in the control group (P = .035). No difference was seen in the frequency of hip osteoporosis (85.4% v 82.9%; P = .92). Baseline BMD measurement had a predictive value of 18 of 24 patients (75%) who developed osteoporosis had osteopenia of the lumbar spine at baseline.

Conclusion

Three years of clodronate therapy significantly reduces the incidence of lumbar spine osteoporosis. Patients at risk of developing osteoporosis are among those who have pretreatment osteopenia, that is, baseline BMD measurement has predictive value.
Racial Composition of Hospitals: Effects on Surgery for Early-Stage Non–Small-Cell Lung Cancer
Authors: Lathan Christopher S. , Neville Bridget A. , Earle Craig C.
Published: September 2008

Purpose

Black patients undergo potentially curative surgery for early-stage lung cancer at a lower rate when compared with white patients. Our study examines the relationship between the percentage of black patients treated at a hospital to determine whether it affects the likelihood of obtaining cancer-directed surgery for patients with non–small-cell lung cancer (NSCLC).

Patients and Methods

We examined claims data of Medicare-eligible patients with nonmetastatic NSCLC living in areas monitored by the Surveillance, Epidemiology, and End Results program between 1991 and 2001. Hospitals were categorized by the percentage of black patients seen: ≤ 8%, more than 8% to 29%, and ≥ 30%. Logistic regression with clustering analysis was used to calculate the odds of undergoing surgical resection.

Results

Among 9,688 patients with NSCLC, 59% of white patients were seen at a hospital that had ≤ 8% black patients, whereas 60% of black patients were seen in hospitals that had ≥ 30% black patients. Regression analysis revealed that hospital racial composition of 30% or greater black patients had a significant negative effect on the likelihood of undergoing surgery for all patients (odds ratio [OR] = 0.71; 95% CI, 0.57 to 0.87), with black race (OR = 0.69; 95% CI, 0.56 to 0.85) and being seen at a low-volume hospital (OR = 0.64; 95% CI, 0.0.49 to 0.83) having a significant negative impact on likelihood of undergoing surgery.

Conclusion

Our study results indicate that patient and hospital characteristics are significant predictors of undergoing surgery for Medicare beneficiaries with localized lung cancer. Further examination of the role of the patient-, provider-, and hospital-level factors, in association with the decision to pursue surgical treatment of localized lung cancers, is needed.
Irinotecan Plus Carboplatin Versus Oral Etoposide Plus Carboplatin in Extensive Small-Cell Lung Cancer: A Randomized Phase III Trial
Authors: Hermes Andreas , Bergman Bengt , Bremnes Roy , Ek Lars , Fluge Sverre , Sederholm Christer , Sundstrøm Stein , Thaning Lars , Vilsvik Jan , Aasebø Ulf , Sörenson Sverre
Published: September 2008

Purpose

A Japanese randomized trial showed superior survival for patients with extensive-disease (ED) small-cell lung cancer (SCLC) receiving irinotecan plus cisplatin compared with etoposide plus cisplatin. The present trial evaluated the efficacy of irinotecan plus carboplatin (IC) compared with oral etoposide plus carboplatin (EC).

Patients and Methods

Patients with ED SCLC were randomly assigned to receive either IC, which consisted of carboplatin (area under the curve = 4; Chatelut formula) and irinotecan (175 mg/m2) intravenously both on day 1, or EC, which consisted of carboplatin as in IC and etoposide (120 mg/m2/d) orally on days 1 through 5. Courses were repeated every 3 weeks with four cycles planned. Doses were reduced by one third in patients with a WHO performance status (PS) of 3 to 4 and/or age older than 70 years. Primary end point was overall survival (OS). Secondary end points were quality of life (QOL) and complete response (CR) rate.

Results

Of 220 randomly assigned patients, 209 were eligible for analysis (IC, n = 105; EC, n = 104). Thirty-five percent were older than 70 years, and 47% had a PS of 2 to 4. The groups were well balanced with respect to prognostic factors. OS was inferior in the EC group (hazard ratio = 1.41; 95% CI, 1.06 to 1.87; P = .02). Median survival time was 8.5 months for IC compared with 7.1 months for EC. One-year survival rate was 34% for IC and 24% for EC. CR was seen in 18 IC patients compared with seven EC patients (P = .02). There were no statistically significant differences in hematologic grade 3 or 4 toxicity. Grade 3 or 4 diarrhea was more common in the IC group. QOL differences were small, with a trend toward prolonged palliation with the IC regimen.

Conclusion

IC prolongs survival in ED SCLC with slightly better scores for QOL.
Unrelated Donor Bone Marrow Transplantation for Children With Acute Myeloid Leukemia Beyond First Remission or Refractory to Chemotherapy
Authors: Bunin Nancy J. , Davies Stella M. , Aplenc Richard , Camitta Bruce M. , DeSantes Kenneth B. , Goyal Rakesh K. , Kapoor Neena , Kernan Nancy A. , Rosenthal Joseph , Smith Franklin O. , Eapen Mary
Published: September 2008

Purpose

Identify prognostic factors that influence outcome after unrelated donor bone marrow transplantation in children with acute myeloid leukemia (AML).

Patients and Methods

Included are 268 patients (age ≤ 18 years) with AML in second complete remission (n = 142), relapse (n = 90), or primary induction failure (n = 36) at transplantation. All patients received bone marrow grafts from an unrelated donor and a myeloablative conditioning regimen. Cox regression models were constructed to identify risk factors that influence outcome after transplantation.

Results

In this analysis, the only risk factor that predicted leukemia recurrence and overall and leukemia-free survival was disease status at transplantation. The 5-year probabilities of leukemia-free survival were 45%, 20%, and 12% for patients who underwent transplantation at second complete remission, relapse, and primary induction failure, respectively. As expected, risk of acute but not chronic graft-versus-host disease (GVHD) was lower with T-cell–depleted bone marrow grafts; T-cell–depleted grafts were not associated with higher risks of leukemia recurrence. We observed similar risks of leukemia relapse in patients with and without acute and chronic GVHD.

Conclusion

Children who underwent transplantation in remission had a superior outcome compared with children who underwent transplantation during relapse or persistent disease. Nevertheless, 20% of children who underwent transplantation in relapse are long-term survivors, suggesting that unrelated donor bone marrow transplantation is an effective therapy in a significant proportion of children with recurrent or primary refractory AML.
Diabetes and Mortality in Men With Locally Advanced Prostate Cancer: RTOG 92-02
Authors: Smith Matthew R. , Bae Kyounghwa , Efstathiou Jason A. , Hanks Gerald E. , Pilepich Miljenko V. , Sandler Howard M. , Shipley William U.
Published: September 2008

Purpose

Diabetes is associated with lower risk of prostate cancer. Most men with diabetes are obese, and obesity is associated with greater prostate cancer mortality. Whether diabetes influences outcomes after prostate cancer diagnosis is unknown.

Patients and Methods

We assessed the relationship between prevalent diabetes and mortality using data from Radiation Therapy Oncology Group Protocol 92-02, a large randomized trial of men (N = 1,554) treated with radiation therapy and short-term versus long-term adjuvant goserelin for locally advanced prostate cancer. Regression and proportional hazard models were performed to evaluate relationships between prevalent diabetes and all-cause mortality, prostate cancer mortality, and non–prostate cancer mortality. Covariates included age, race, tumor stage, Gleason score, prostate-specific antigen, weight, and treatment arm.

Results

There were a total of 765 deaths; 210 (27%) were attributed to prostate cancer. In univariate analyses, prevalent diabetes was associated with greater all-cause mortality and non–prostate cancer mortality but not prostate cancer mortality. After controlling for other covariates, prevalent diabetes remained significantly associated with greater all-cause mortality and non–prostate cancer mortality (hazard ratio [HR] = 2.12; 95% CI, 1.69 to 2.66; P < .0001) but not prostate cancer mortality (HR = 0.80; 95% CI, 0.51 to 1.25; P = .34). In contrast, weight was associated with greater prostate cancer mortality (HR = 1.77; 95% CI, 1.22 to 2.55; P = .002) but not all-cause or non–prostate cancer mortality.

Conclusion

Weight but not prevalent diabetes is associated with greater prostate cancer mortality in men receiving combined modality treatment for locally advanced disease. These observations suggest that the association between obesity and greater prostate cancer mortality is mediated by mechanism(s) other than the characteristic metabolic alterations of diabetes.
Clinical and Pathologic Characteristics of Patients With BRCA-Positive and BRCA-Negative Breast Cancer
Authors: Atchley Deann P. , Albarracin Constance T. , Lopez Adriana , Valero Vicente , Amos Christopher I. , Gonzalez-Angulo Ana Maria , Hortobagyi Gabriel N. , Arun Banu K.
Published: September 2008

Purpose

Mutations in the BRCA1 and BRCA2 genes confer greater risk of developing breast cancer. We determined whether tumor pathologic features and clinical features differ in patients with and without BRCA mutations.

Patients and Methods

Tumor pathologic features and clinical characteristics were examined in 491 women with breast cancer who underwent genetic testing for BRCA mutations between 1997 and 2006. A retrospective review of medical records was conducted to determine clinical characteristics including ethnicity, age and clinical stage at diagnosis, age at parity, number of full-term pregnancies, use of oral contraceptives and hormone replacement therapy, and BRCA mutation status. Tumor pathology was reviewed to determine histologic type, tumor grade, and estrogen receptor, progesterone receptor, and HER-2/neu status.

Results

Of the 491 patients with identified breast cancers, 391 patients were BRCA negative, and 86 patients were BRCA positive. Triple-negative breast cancer (ie, those with negative estrogen receptor, progesterone receptor, and HER-2/neu status) was diagnosed in 57.1% of the BRCA1-positive patients, 23.3% of the BRCA2-positive patients, and 13.8% of the BRCA-negative patients. BRCA1 mutation carriers had higher nuclear grade tumors than the other two groups (P < .001). Of the triple-negative cancer patients, BRCA2 mutation carriers were older when diagnosed than BRCA1 mutation carriers and noncarriers (P < .01).

Conclusion

These results suggest that tumors associated with BRCA1 mutations may be divided into two distinct groups, triple-negative and non–triple-negative groups. Future studies should seek to determine whether patients with BRCA1 mutations and triple-negative breast cancer respond to treatment better than BRCA-negative patients with similar tumor pathology.
Efficacy of RAD001 (Everolimus) and Octreotide LAR in Advanced Low- to Intermediate-Grade Neuroendocrine Tumors: Results of a Phase II Study
Authors: Yao James C. , Phan Alexandria T. , Chang David Z. , Wolff Robert A. , Hess Kenneth , Gupta Sanjay , Jacobs Carmen , Mares Jeannette E. , Landgraf Andrea N. , Rashid Asif , Meric-Bernstam Funda
Published: September 2008

Purpose

Evaluate the activity of everolimus (RAD001) in combination with octreotide long-acting repeatable (LAR) in patients with advanced low- to intermediate-grade neuroendocrine tumors.

Methods

Treatment consisted of RAD001 5 mg/d (30 patients) or 10 mg/d (30 patients) and octreotide LAR 30 mg every 28 days. Thirty carcinoid and 30 islet cell patients were enrolled.

Results

Intent-to-treat response rate was 20%. Per protocol, there were 13 with partial responses (22%), 42 with stable disease (SD; 70%), and five patients with progressive disease (8%). Overall median progression-free survival (PFS) was 60 weeks. Median PFS for patients with known SD at entry was longer than for those who had progressive disease (74 v 50 weeks; P < .01). Median overall survival has not been reached. One-, 2-, and 3-year survival rates were 83%, 81%, and 78%, respectively. Among 37 patients with elevated chromogranin A, 26 (70%) achieved normalization or more than 50% reduction. Most common toxicity was mild aphthous ulceration. Grade 3/4 toxicities occurring in ≥ 10% of patients included hypophosphatemia (11%), fatigue (11%), and diarrhea (11%). Treatment was associated with a dose-dependent rise in lactate dehydrogenase (LDH). Those with lower than 109 U/L rise in LDH at week 4 had shorter PFS (38 v 69 weeks; P = .01). Treatment was also associated with a decrease in proliferation marker Ki-67 among patients who underwent optional paired pre- and post-treatment biopsy (P = .04).

Conclusion

RAD001 at 5 or 10 mg/d was well tolerated in combination with octreotide LAR, with promising antitumor activity. Confirmatory studies are ongoing.
Nanosized Polymer Particle-facilitated Preparation of Mesoporous Silica Particles Using a Spray Method
Authors: Nandiyanto Asep Bayu Dani , Iskandar Ferry , Okuyama Kikuo
Published: September 2008

Spherical silica particles with large mesopores and controlled particle size in the submicron range were prepared using a mixed solution of silica nanoparticles and nanosized polymer particle as a template via spray routes.
Iron Catalyst for Oxidation in Water: Surfactant-type Iron Complex-catalyzed Mild and Efficient Oxidation of Aryl Alkanes Using Aqueous TBHP as Oxidant in Water
Authors: Nagano Takashi , Kobayashi Shu
Published: September 2008

Surfactant-type iron(III) complex, Fe2O(DS)4, was found to be effective for benzylic oxidation of simple aryl alkanes using aqueous t-butyl hydroperoxide (TBHP) as an oxidant.
1-(Organoselanyl)perfluoroalkanols: A Stable and Efficient Precursor for Organoselenols
Authors: Yamamoto Teruhisa , Moriura Eri , Sawa Arisa , Yoshimatsu Mitsuhiro
Published: September 2008

The 1-(organoselanyl)perfluoroalkanols 1, 3, 4, and 10 were successfully prepared and reactions with hexanoyl chlorides to produce the corresponding esters 5, 7, and 8, accompanied by the selenoesters 6 were conducted. The DBU-mediated alkylations of the heptafluorobutanols 4, 10, and the α-p-nitrobenzoate 2 with alkyl halides easily provided alkyl phenyl selenides 9a–9i and 11a–11c in good to high yields.
Reaction between Guanidine Hydrochloride and Chalcones: An Efficient Solvent-free Synthesis of 2,4,6-Triarylpyridines under Microwave Irradiation
Authors: Adib Mehdi , Mohammadi Bagher , Rahbari Sahar , Mirzaei Peiman
Published: September 2008

A series of 2,4,6-triarylpyridines have been synthesized via an efficient solvent-free reaction between guanidine hydrochloride and chalcones under microwave irradiation in excellent yields.
Fabrication of Free-standing Layer-by-layer Films of Layered Double Hydroxide Nanosheets and Polyelectrolytes
Authors: Chen Xu , Lei Yu , Yang Wensheng
Published: September 2008

Free-standing films of layered double hydroxide nanosheets and polyelectrolytes were fabricated via layer-by-layer self-assembly techniques and further substrate erosion methods. The obtained films were ultrathin and showed excellent flexibility, good transparency, and high thermal stability.
Highly Selective Production of 2-Adamantanone by Photocatalytic Oxidation of Adamantane
Authors: Song Sun-Jung , Kim Kyoung Seok , Kim Kyung Hwan , Kim Jong Beom , Kim Jong-Ho , Kim Keun-Sik , Shin Honghyun , Cho Dong Lyun
Published: September 2008

2-Adamantanone was selectively produced by photocatalytic oxidation of adamantane in acetic acid using TiO2 powders. The reactions were carried out at ambient and acetic acid reflux temperatures with and without an oxidant. Adding oxidant in refluxing acetic acid under irradiation remarkably increased conversion and selectivity. Rutile TiO2 powders showed better conversion and selectivity in the presence of H2O2. The total conversion was 67% and the highest selectivity of 2-adamantanone was 89%.
Evaluation of Chiral Amino Acid Discrimination by a Permethylated Cyclic Tetrasaccharide, cyclo-{→6)-α-d-Glcp-(1→3)-α-d-Glcp-(1→6)-α-d-Glcp-(1→3)-α-d-Glcp-(1→}, Using FAB Mass Spectrometry
Authors: Shizuma Motohiro , Kiso Taro , Terauchi Hisashi , Takai Yoshio , Yamada Hitoshi , Nishimoto Tomoyuki , Ono Daisuke , Shimomura Osamu , Nomura Ryoki , Miwa Yoshikatsu , Nakamura Masaki , Nakano Hirofumi
Published: September 2008

The novel cyclic oligosaccharide, permethylated tetrasaccharide (CTS), determinates the enantiomers of chiral amino acid isopropyl ester hydrochlorides.
Fabrication of Porous Nanoscale Polyimide Structures
Authors: Kasai Hitoshi , Mitsui Hideharu , Zhao Gufan , Ishizaka Takayuki , Suzuki Masao , Oikawa Hidetoshi , Nakanishi Hachiro
Published: September 2008

In the fabrication of polyimide (PI) spherical nanoparticles by the reprecipitation method, intriguing uniquely shaped objects, including doughnut-like and/or hollow, and polymeric soccer ball-shaped PI nanoparticles are rarely obtained. Furthermore, PI fine particles, which possess a hollow core and some 100 nm-sized surface pores leading to the inner hollow, were reproducibly obtained by the improved reprecipitation method.