bluuebunny/crossref_metadata_2025 huggingface dataset:
Search and Evaluation Strategies for Effective Use of World Wide Web in Leadership Education
Authors: Langone Christine A.
Published: August 2007

Executive Summary Educators and students of leadership have access to a dynamic tool in the World Wide Web. However, with the increasing amount of information available, finding specific information for teaching, learning, and research in a timely manner can become a challenge. As a teaching/learning tool, Web-based resources must ultimately contribute to learning amid abundant commercial and recreational material. This article offers guidelines for encouraging effective search strategies, provides resources both on-line and in print for further exploration, and presents a Web Evaluation Tool which outlines criteria for evaluation of Web sites for educational use. Students knowledgeable of effective search strategies can enhance their study of leadership, and continue to update their leadership information, research, and trends through access to relevant and useful resources readily available on the Web.
Flying High with Herb Kelleher: A Profile in Charismatic Leadership
Authors: Gibson Jane Whitney , Blackwell Charles W.
Published: August 2007

Executive Summary Herb Kelleher, co-founder, CEO, President and Chairman of Southwest Airlines is cited in this article as an ideal example of charismatic leadership at its best. A discussion of charismatic leadership focuses on traits and behaviors of charismatic leaders. This model is then used to examine Kelleher's traits and behaviors at Southwest Airlines, named in 1998 as the best place to work in America by Fortune Magazine. Kelleher's vision and style are seen as the driving forces of this maverick airline which has consistently posted a profit for 26 consecutive years and does things differently than any other company in the industry. The key to Southwest's success is largely thought to be the warmth and determination of its employees who mirror those same qualities in their leader. The article includes Kelleher's thoughts on leadership and concludes that there is reason to question whether the strong, personality-driven Southwest culture can survive after Kelleher retires from the helm.
Special Section: On Learning from Experience: Personal and Private Experiences as the Context for Psychotherapeutic Practice
Authors: Jensen Per
Published: August 2007

The central idea in evidence-based practice is that it is the therapy that works and not the therapist. However, this article seeks to show how both our private and personal lives are an area for reflection when we are working as psychotherapists, and that personal and private experience can be an important framework for practising psychotherapy. Through looking at elements of the personal and private lives of three different therapists in the light of a therapy session conducted by each, I will try to demonstrate how personal and private experiences may influence clinical practice. The article builds on an ongoing grounded theory research project at the Tavistock Centre, London.
Making sense of police reforms
Authors: Chan Janet
Published: July 2007

Sensemaking is an ongoing process members of organizations engage in to explicate their world. When faced with changes in their environment, members try to make sense of uncertainties and disruptions and `enact' their interpretations into the world to give it a sense of order. This article draws on a longitudinal study of police recruits to describe how officers make sense of reforms that have considerably altered the field of policing. It argues that sensemaking provides a processual frame that helps connect Bourdieu's concepts of field and habitus : it describes how agents translate changes in the field into shared understandings and values that inform the occupational habitus. Sensemaking is thus an important element for the theorizing of police culture and practice.
Fractured neck of femur - solving the unsolved fracture
Authors: Parker Martyn
Published: August 2007

The choice of treatment for an intracapsular fracture can only be made on an individual patient basis. Factors that influence this decision are the facilities available, surgical expertise, degree of displacement of the fracture, delay from fracture to surgery and age of the patient. In addition, the presence of other medical conditions that may influence fracture healing or adversely affect arthroplasty need to be considered. The clinician when faced with a patient with an intracapsular fracture must assess each patient's individual risk factors, and then decide if the risk of failure of internal fixation of the fracture is high enough to justify replacing the femoral head with an arthroplasty.
More Haste, Less Speed? An Evaluation of Fast Track Policies to Tackle Persistent Youth Offending in Scotland
Authors: Hill Malcolm , Walker Moira , Moodie Kristina , Wallace Brendan , Bannister Jon , Khan Furzana , McIvor Gill , Kendrick Andrew
Published: July 2007

In 2003 the Scottish Executive introduced a new `Fast Track' policy on a pilot basis, which was intended to speed up the processing of persistent youth offending cases and reduce rates of persistent offending. Additional resources were provided to promote access to dedicated programmes, as well as quicker assessment, report delivery and decision making. This paper, based on a multi-stranded comparative evaluation, describes how the policy was welcomed by a wide range of practitioners, decision makers and managers involved with children's hearings who mostly thought it was a positive innovation consistent with the hearing system's commitment to a welfare-based approach. `Fast Track' cases were handled more quickly than others. After two years, however, the policy was discontinued, largely because of negative evidence about re-offending.
Small Talk Makes a Big Difference: Recent Developments in Interactive, SMS-Based Television
Authors: Beyer Yngvil , Enli Gunn Sara , Maasø Arnt Johan , Ytreberg Espen
Published: August 2007

The article discusses key features of SMS-based television. It has a particular focus on the shift from one-way broadcast communication toward two-way interactivity, and on new forms of user participation through SMS-based television's interactive design interfaces. The article presents a multimodal analysis of design in SMS-based television formats, a discourse analysis of their roles and interactions, and a typology of their degrees of interactivity. It also draws on interviews with industry decision-makers and on relevant statistics. The article develops a conceptual interest, introducing some neologisms to account for the original textual features of SMS-based television. Its designs are analyzed using a concept of “zones,” while its roles and interactions are seen as linking these zones by means of “axes.” In closing it is suggested that SMS-based television presents us with interactivity as a realized, albeit mundane, fact rather than as a future promise.
The Changing Shape of the Culture Industry; or, How Did Electronica Music Get into Television Commercials?
Authors: Taylor Timothy D.
Published: August 2007

This article examines the recent changes in the culture industry and demographics that permitted a formerly underground music to enter the mainstream. The demographic shift concerns the group that Pierre Bourdieu calls the “new petite bourgeoisie,” which in the 1980s began to use the music of their youth in commercials, signaling the beginning of the end of the commercial jingle, as well as the stigma that once attached to musicians who permitted their music be in advertising. But the yuppie baby boom generation that inhabited the new petite bourgeoisie has been succeeded by a younger group in the advertising industry, whose representatives are helping to bring underground electronic popular musics to mass audiences in television commercials. Automobile manufacturers in particular have gravitated toward this music.
The self-directed learning readiness of first year bachelor of nursing students
Authors: Smedley Alison
Published: July 2007

Self-directed learning (SDL) has evolved as a method of learning into Australian nurse education over the past few years with enthusiastic claims of increasing student numbers and access to learning. It is an educational concept and transformative learning process that has been used increasingly in adult education, especially within tertiary institutions. Most tertiary educational institutions now offer components of their nursing programmes using self-directed learning methods that may include distance programmes, blended mode or flexible delivery, clinical learning logs and independent learning contracts or problem based packages. This paper reports on research that evaluated the self-directed learning readiness of undergraduate student nurses in their first year of the Bachelor of Nursing (BN) programme within a private tertiary education institution in Sydney, Australia. These findings were compared to research undertaken with beginning degree students in a large public university nurse education programme in Sydney and identified remarkably similar results. Results from both studies were similar and highlight the need for curriculum developers to include strategies in beginning level degree subjects to cultivate self-directed learning skills for nurses.
Exosomes released from macrophages infected with intracellular pathogens stimulate a proinflammatory response in vitro and in vivo
Authors: Bhatnagar Sanchita , Shinagawa Kazuhiko , Castellino Francis J. , Schorey Jeffrey S.
Published: August 2007

Intracellular pathogens and the molecules they express have limited contact with the immune system. Here, we show that macrophages infected with intracellular pathogens Mycobacterium tuberculosis, M bovis BCG, Salmonella typhimurium, or Toxoplasma gondii release from cells small vesicles known as exosomes which contain pathogen-associated molecular patterns (PAMPs). These exosomes, when exposed to uninfected macrophages, stimulate a proinflammatory response in a Toll-like receptor– and myeloid differentiation factor 88–dependent manner. Further, exosomes isolated from the bronchoalveolar lavage fluid (BALF) of M bovis BCG–infected mice contain the mycobacteria components lipoarabinomannan and the 19-kDa lipoprotein and can stimulate TNF-α production in naive macrophages. Moreover, exosomes isolated from M bovis BCG– and M tuberculosis–infected macrophages, when injected intranasally into mice, stimulate TNF-α and IL-12 production as well as neutrophil and macrophage recruitment in the lung. These studies identify a previously unknown function for exosomes in promoting intercellular communication during an immune response to intracellular pathogens, and we hypothesize that extracellular release of exosomes containing PAMPs is an important mechanism of immune surveillance.
Docetaxel, Cisplatin, and Fluorouracil; Docetaxel and Cisplatin; and Epirubicin, Cisplatin, and Fluorouracil As Systemic Treatment for Advanced Gastric Carcinoma: A Randomized Phase II Trial of the Swiss Group for Clinical Cancer Research
Authors: Roth Arnaud D. , Fazio Nicola , Stupp Roger , Falk Stephen , Bernhard Jürg , Saletti Piercarlo , Köberle Dieter , Borner Markus M. , Rufibach Kaspar , Maibach Rudolf , Wernli Martin , Leslie Martin , Glynne-Jones Robert , Widmer Lukas , Seymour Matthew , de Braud Filippo
Published: July 2007

Purpose

This randomized phase II trial evaluated two docetaxel-based regimens to see which would be most promising according to overall response rate (ORR) for comparison in a phase III trial with epirubicin-cisplatin-fluorouracil (ECF) as first-line advanced gastric cancer therapy.

Patients and Methods

Chemotherapy-naïve patients with measurable unresectable and/or metastatic gastric carcinoma, a performance status ≤ 1, and adequate hematologic, hepatic, and renal function randomly received ≤ eight 3-weekly cycles of ECF (epirubicin 50 mg/m2 on day 1, cisplatin 60 mg/m2 on day 1, and fluorouracil [FU] 200 mg/m2/d on days 1 to 21), TC (docetaxel initially 85 mg/m2 on day 1 [later reduced to 75 mg/m2 as a result of toxicity] and cisplatin 75 mg/m2 on day 1), or TCF (TC plus FU 300 mg/m2/d on days 1 to 14). Study objectives included response (primary), survival, toxicity, and quality of life (QOL).

Results

ORR was 25.0% (95% CI, 13% to 41%) for ECF, 18.5% (95% CI, 9% to 34%) for TC, and 36.6% (95% CI, 23% to 53%) for TCF (n = 119). Median overall survival times were 8.3, 11.0, and 10.4 months for ECF, TC, and TCF, respectively. Toxicity was acceptable, with one toxic death (TC arm). Grade 3 or 4 neutropenia occurred in more treatment cycles with docetaxel (TC, 49%; TCF, 57%; ECF, 34%). Global health status/QOL substantially improved with ECF and remained similar to baseline with both docetaxel regimens.

Conclusion

Time to response and ORR favor TCF over TC for further evaluation, particularly in the neoadjuvant setting. A trend towards increased myelosuppression and infectious complications with TCF versus TC or ECF was observed.
Quality of Life With Docetaxel Plus Cisplatin and Fluorouracil Compared With Cisplatin and Fluorouracil From a Phase III Trial for Advanced Gastric or Gastroesophageal Adenocarcinoma: The V-325 Study Group
Authors: Ajani Jaffer A. , Moiseyenko Vladimir M. , Tjulandin Sergei , Majlis Alejandro , Constenla Manuel , Boni Corrado , Rodrigues Adriano , Fodor Miguel , Chao Yee , Voznyi Edouard , Awad Lucile , Van Cutsem Eric
Published: July 2007

Purpose

Therapy of patients with advanced gastric or gastroesophageal junction cancer should provide symptom relief and improve quality of life (QOL) because most patients are symptomatic at baseline. Using validated instruments, we prospectively assessed QOL (even after completion of protocol treatment) as one of the secondary end points of the V325 phase III trial.

Patients and Methods

Four hundred forty-five patients randomly received either docetaxel 75 mg/m2 and cisplatin 75 mg/m2 each on day 1 plus fluorouracil 750 mg/m2/d continuous infusion on days 1 to 5 every 3 weeks (DCF) or cisplatin 100 mg/m2 on day 1 plus fluorouracil 1,000 mg/m2/d continuous infusion on days 1 to 5 every 4 weeks (CF). The European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C30 (EORTC QLQ-C30) and, where available, the EuroQOL EQ-5D questionnaire were administered every 8 weeks from baseline until progression and then every 3 months. Time to definitive deterioration of QOL parameters was analyzed.

Results

The proportions of patients having assessable EORTC QLQ-C30 and EQ-5D questionnaires at baseline were 86.0% and 78.7% with DCF, respectively, and 89.7% and 92.8% with CF, respectively. Time to 5% deterioration of global health status (primary end point) significantly favored DCF over CF (log-rank test, P = .01). QOL was preserved longer for patients on DCF than those on CF for all time to deterioration analyses, demonstrating the statistical superiority of DCF compared with CF.

Conclusion

V325 represents the largest trial with the longest prospectively controlled evaluations of QOL during protocol chemotherapy and follow-up in patients with advanced gastric or gastroesophageal junction cancer. In V325, advanced gastric or gastroesophageal junction cancer patients receiving DCF not only had statistically improved overall survival and time to tumor-progression, but they also had better preservation of QOL compared with patients receiving CF.
Molecularly Targeted Oncology Therapeutics and Prolongation of the QT Interval
Authors: Strevel Elizabeth L. , Ing Douglas J. , Siu Lillian L.
Published: July 2007

Investigation and utilization of molecularly targeted agents has induced a number of drug adverse effects that are not typically associated with conventional chemotherapy. QT interval prolongation, a cardiac toxicity that increases the risk of fatal arrhythmia, is associated with several novel oncology therapies. Classes of molecularly targeted agents with described QT effects include histone deacetylase inhibitors, multitargeted tyrosine kinase inhibitors, vascular disruption agents, farnesyl protein transferase inhibitors, Src/Abl kinase inhibitors, and protein kinase C inhibitors. Concurrently, guidelines for monitoring the QT-prolonging effects of drugs under development have become increasingly rigorous. Although these guidelines apply to anticancer agents, they were not specifically designed for the oncology patient population. This article will review the pathophysiology of QT prolongation, methods of preclinical QT assessment, and current guidelines for QT evaluation in early phase trials. Additionally, molecularly targeted agents with QT effects will be summarized, and mechanisms of addressing this toxicity in the context of oncology drug development will be explored.
Reintroduction of Oxaliplatin Is Associated With Improved Survival in Advanced Colorectal Cancer
Authors: de Gramont Aimery , Buyse Marc , Abrahantes Jose Cortinas , Burzykowski Tomasz , Quinaux Emmanuel , Cervantes Andres , Figer Arie , Lledo Gérard , Flesch Michel , Mineur Laurent , Carola Elisabeth , Etienne Pierre-Luc , Rivera Fernando , Chirivella Isabel , Perez-Staub Nathalie , Louvet Christophe , André Thierry , Tabah-Fisch Isabelle , Tournigand Christophe
Published: July 2007

Purpose

In the OPTIMOX1 trial, previously untreated patients with advanced colorectal cancer were randomly assigned to two different schedules of leucovorin, fluorouracil, and oxaliplatin that were administered until progression in the control arm or in a stop-and-go fashion in the experimental arm. The randomly assigned treatment groups did not differ significantly in terms of response rate, progression-free survival, and overall survival (OS). However, the impact of oxaliplatin reintroduction on OS was potentially masked by the fact that a large number of patients did not receive the planned oxaliplatin reintroduction or received oxaliplatin after second-line therapy in both treatment groups.

Patients and Methods

A Cox model was fitted with all significant baseline factors plus time-dependent variables reflecting tumor progression, reintroduction of oxaliplatin, and use of second-line irinotecan. A shared frailty model was fitted with all significant baseline factors plus the number of lines of chemotherapy received by the patient and the percentage of patients with oxaliplatin reintroduction in the center. An adjusted hazard ratio (HR) was calculated for three reintroduction classes (1% to 20%, 21% to 40%, and > 40%), using centers with no reintroduction (0%) as the reference group.

Results

Oxaliplatin reintroduction had an independent and significant impact on OS (HR = 0.56, P = .009). The percentage of patients with oxaliplatin reintroductions also had a significant impact on OS. Centers in which more than 40% of the patients were reintroduced had an adjusted HR for OS of 0.59 compared with centers in which no patient was reintroduced.

Conclusion

Oxaliplatin reintroduction is associated with improved survival in patients with advanced colorectal cancer.
Survival Prediction in Terminally Ill Cancer Patients by Clinical Estimates, Laboratory Tests, and Self-Rated Anxiety and Depression
Authors: Gripp Stephan , Moeller Sibylle , Bölke Edwin , Schmitt Gerd , Matuschek Christiane , Asgari Sonja , Asgharzadeh Farzin , Roth Stephan , Budach Wilfried , Franz Matthias , Willers Reinhardt
Published: July 2007

Purpose

To study how survival of palliative cancer patients relates to subjective prediction of survival, objective prognostic factors (PFs), and individual psychological coping.

Patients and Methods

Survival was estimated according to three categories (< 1 month, 1 to 6 months, and > 6 months) by two physicians (A and B) and the institutional tumor board (C) for 216 patients recently referred for palliative radiotherapy. After 6 months, the accuracy of these estimates was assessed. The prognostic relevance of clinical symptoms, performance status, laboratory tests, and self-reported emotional distress (Hospital Anxiety and Depression Scale) was investigated.

Results

In 61%, 55%, and 63% of the patients, prognoses were correctly estimated by A, B, and C, respectively. κ statistic showed fair agreement of the estimates, which proved to be overly optimistic. Accuracy of the three estimates did not improve with increasing professional experience. In particular, the survival of 96%, 71%, and 87% of patients who died in less than 1 month was overestimated by A, B, and C, respectively. On univariate analysis, 11 of 27 parameters significantly affected survival, namely performance status, primary cancer, fatigue, dyspnea, use of strong analgesics, brain metastases, leukocytosis, lactate dehydrogenase (LDH), depression, and anxiety. On multivariate analysis, colorectal and breast cancer had a favorable prognosis, whereas brain metastases, Karnofsky performance status less than 50%, strong analgesics, dyspnea, LDH, and leukocytosis were associated with a poor prognosis.

Conclusion

This study revealed that physicians' survival estimates were unreliable, especially in the case of patients near death. Self-reported emotional distress and objective PFs may improve the accuracy of survival estimates.
Tumor Sclerosis but Not Cell Proliferation or Malignancy Grade Is a Prognostic Marker in Advanced-Stage Follicular Lymphoma: The German Low Grade Lymphoma Study Group
Authors: Klapper Wolfram , Hoster Eva , Rölver Lars , Schrader Carsten , Janssen Dirk , Tiemann Markus , Bernd Heinz-Wolfram , Determann Olaf , Hansmann Martin-Leo , Möller Peter , Feller Alfred , Stein Harald , Wacker Hans-Heinrich , Dreyling Martin , Unterhalt Michael , Hiddemann Wolfgang , Ott German
Published: July 2007

Purpose

Follicular lymphoma is an indolent lymphoma with a long median overall survival. However, a considerable number of patients die within the first 2 years after the onset of the disease. Because the treatment options vary with respect to antitumor effect and potential toxic adverse effects, the identification of high-risk patients would be helpful in directing therapeutic decisions in individual patients. Several histopathologic biomarkers for risk stratification have been suggested, but most markers have not been validated in patients treated in prospective trials.

Patients and Methods

We report a comprehensive approach to evaluate histopathologic biomarkers, including WHO grade, histology, and proliferation and quantitation of immune bystander cells, in 158 patients with nodal advanced-stage follicular lymphoma treated first line within a randomized trial.

Results

Tumor sclerosis was a significant prognostic marker of poor overall survival that was independent of the Follicular Lymphoma International Prognostic Index (FLIPI). WHO grade, proliferation, and total T-cell or macrophage content were not associated with overall survival.

Conclusion

The presence of sclerosis within the lymphoma is a marker of poor overall survival that is independent of the FLIPI. The quantification of macrophage or absolute T-cell content, grading, and proliferation are of no help in predicting the outcome of FL. Future studies need to identify surrogate markers for the prognostic immune signatures identified by gene expression profiling. Most importantly, new prognostic markers need to be confirmed in patients treated within prospective trials.
Phase II Trial of Sorafenib Plus Interferon Alfa-2b As First- or Second-Line Therapy in Patients With Metastatic Renal Cell Cancer
Authors: Gollob Jared A. , Rathmell W. Kimryn , Richmond Tina M. , Marino Christine B. , Miller Elizabeth K. , Grigson Gayle , Watkins Catharine , Gu Lin , Peterson Bercedis L. , Wright John J.
Published: July 2007

Purpose

We undertook this study to determine the activity and tolerability of sorafenib administered with interferon alfa-2b (IFN-α-2b) as first- or second-line therapy in metastatic renal cell cancer (RCC).

Patients and Methods

Between November 2004 and October 2006, 40 patients at two sites were enrolled onto a phase II trial of sorafenib plus IFN-α-2b. Treatment consisted of 8-week cycles of sorafenib 400 mg orally bid plus IFN-α-2b 10 million U subcutaneously three times a week followed by a 2-week break. Patients were eligible to receive additional cycles of therapy until disease progression. Dose reduction of both drugs by 50% was permitted once for toxicity.

Results

The response rate was 33% (95% CI, 19% to 49%; 13 of 40 patients), including 28% partial responses (n = 11) and 5% complete responses (n = 2). Responses were seen in treatment-naïve and interleukin-2 (IL-2) –treated patients within the first two cycles. The median duration of response was 12 months. With a median follow-up time of 14 months, median progression-free survival time was 10 months (95% CI, 8 to 18 months), and median overall survival time has not yet been reached. Fatigue, anorexia, anemia, diarrhea, hypophosphatemia, rash, nausea, and weight loss were the most common toxicities. Grade 3 toxicities were uncommon but included hypophosphatemia, neutropenia, rash, fatigue, and anemia. Dose reductions were required in 65% of patients.

Conclusion

The combination of sorafenib and IFN-α-2b has substantial activity in treatment-naïve and IL-2–treated patients with RCC. The toxicity exceeded that of either drug alone, but dose reductions and breaks between cycles allowed for chronic therapy. A larger, randomized trial would determine whether there is any advantage to this regimen compared with sorafenib alone.
Association between Serum Insulin-Like Growth Factor-I Levels and Thyroid Disorders in a Population-Based Study
Authors: Völzke Henry , Friedrich Nele , Schipf Sabine , Haring Robin , Lüdemann Jan , Nauck Matthias , Dörr Marcus , Brabant Georg , Wallaschofski Henri
Published: August 2007

Objective: There is current debate on whether serum IGF-I levels are associated with thyroid disorders. The aims of the present study were: 1) to investigate possible associations between serum IGF-I levels and thyroid disorders and 2) to analyze the role of serum IGF binding protein (IGFBP)-3 and TSH levels for these associations.

Design: This was a cross-sectional Study of Health in Pomerania.

Setting: The study was conducted in the general population of northeast Germany.

Subjects: The study population comprised 3662 subjects (1746 women) without history of thyroid disorders.

Interventions: No interventions have been performed.

Main Outcome Measures: Goiter and thyroid nodules were determined by ultrasound. Serum TSH levels less than 0.25 mIU/liter were considered decreased.

Results: Adjusted for major confounders and risk factors for thyroid disorders, subjects with serum IGF-I levels above the upper tertile had higher odds for goiter relative to subjects with serum IGF-I levels below the lower tertile [odds ratio (OR) 1.67; 95% confidence interval (CI) 1.24–2.26 in women; OR 2.04; 95% CI 1.55–2.68 in men]. A similar association was present for thyroid nodules in men (OR 1.64; 95% CI 1.17–2.32) and for decreased serum TSH levels in women (OR 1.65; 95% CI 1.00–2.69). Serum IGFBP-3 levels were not associated with thyroid disorders and did not represent effect modifiers for the association between serum IGF-I levels and the endpoints.

Conclusions: We conclude that high serum IGF-I levels are associated with goiter. Whereas high serum IGF-I levels are also related to thyroid nodules in men, they are related to decreased serum TSH levels in women. Serum IGFBP-3 and TSH levels did not modulate these associations.
Insulin-Like Factor 3 Levels in Cord Blood and Serum from Children: Effects of Age, Postnatal Hypothalamic-Pituitary-Gonadal Axis Activation, and Cryptorchidism
Authors: Bay Katrine , Virtanen Helena E. , Hartung Stefan , Ivell Richard , Main Katharina M. , Skakkebaek Niels E. , Andersson Anna-Maria , Toppari Jorma
Published: August 2007

Context: The Leydig cell hormone insulin-like factor 3 (INSL3) is important for testicular descent. Currently INSL3 levels in cord blood, in serum throughout childhood, and in relation to congenital cryptorchidism are unknown.

Objective: The objective of the study was to characterize INSL3 levels in cord blood during the postnatal activation of the hypothalamic-pituitary-gonadal axis and in later childhood in normal boys and girls and cryptorchid boys.

Design and Participants: Serum from 267 3-month-old boys of a prospective study with standardized cryptorchidism classification was analyzed for INSL3 (of these, 99 also had cord blood samples). Testicular position was known in 151 controls and 54 transiently cryptorchid and 62 persistently cryptorchid subjects. Eight infant girls, 26 boys (4.1–10.1 yr), and 13 girls (3.7–8.7 yr) were also included.

Outcome Measure: INSL3, age, testicular position, LH, and testosterone were measured.

Results: INSL3 levels were significantly higher (P < 0.001) in cord blood and 3-month-old boys as compared with older prepubertal boys. At 3 months of age, INSL3 correlated significantly with LH in healthy boys. Cord blood INSL3 was significantly reduced in persistently cryptorchid boys (P = 0.001), and 3-month-old persistently cryptorchid boys had a significantly increased LH to INSL3 ratio (P = 0.014). INSL3 was unmeasurable in girls at all ages.

Conclusions: In boys, early postnatal INSL3 is markedly higher as compared with later childhood, presumably because it is stimulated by the transient postnatal LH peak. INSL3 was unmeasurable in girls at all ages. Reduced cord blood INSL3 and an increased LH to INSL3 ratio at 3 months of age in persistently cryptorchid boys suggest impaired Leydig cell function in cryptorchid boys already in the perinatal period.
Deterioration of Growth Hormone (GH) Response and Anterior Pituitary Function in Young Adults with Childhood-Onset GH Deficiency and Ectopic Posterior Pituitary: A Two-Year Prospective Follow-Up Study
Authors: di Iorgi Natascia , Secco Andrea , Napoli Flavia , Tinelli Carmine , Calcagno Annalisa , Fratangeli Nadia , Ambrosini Linda , Rossi Andrea , Lorini Renata , Maghnie Mohamad
Published: August 2007

Context: The current criteria for definition of partial GHD in young adults are still a subject of debate.

Objectives: The objective of the study was to reinvestigate anterior pituitary function in young adults with congenital childhood-onset GHD associated with structural hypothalamic-pituitary abnormalities and normal GH response at the time of first reassessment of GH secretion.

Design and Setting: This was a prospective explorative study conducted in a university research hospital.

Patients and Methods: Thirteen subjects with a mean age of 17.2 ± 0.7 yr and a peak GH after insulin tolerance test (ITT) higher than 5 μg/liter were recruited from a cohort of 42 patients with childhood-onset GHD and ectopic posterior pituitary at magnetic resonance imaging. GH secretion after ITT and GHRH plus arginine, IGF-I concentration, and body mass index, waist circumference, blood pressure, total cholesterol, and fibrinogen were evaluated at baseline and at 2-yr follow-up.

Results: At mean age of 19.2 ± 0.7 yr, the mean peak GH response decreased significantly after ITT (P = 0.00001) and GHRH plus arginine (P = 0.0001). GH peak values after ITT and GHRH plus arginine were less than 5 and 9 μg/liter in 10 and eight patients, respectively. Additional pituitary defects were documented in eight patients. Significant changes were found in the values of IGF-I sd score (P = 0.0026), waist circumference (P = 0.00001), serum total cholesterol (P = 0.00001), and serum fibrinogen (P = 0.0004).

Conclusions: The results of this study underline the importance of further reassessment of pituitary function in young adults with GHD of childhood-onset and poststimulation GH responses suggestive of partial GHD.
Mammalian Protein-Protein Interaction Trap (MAPPIT) Analysis of STAT5, CIS, and SOCS2 Interactions with the Growth Hormone Receptor
Authors: Uyttendaele Isabel , Lemmens Irma , Verhee Annick , De Smet Anne-Sophie , Vandekerckhove Joël , Lavens Delphine , Peelman Frank , Tavernier Jan
Published: August 2007

Binding of GH to its receptor induces rapid phosphorylation of conserved tyrosine motifs that function as recruitment sites for downstream signaling molecules. Using mammalian protein-protein interaction trap (MAPPIT), a mammalian two-hybrid method, we mapped the binding sites in the GH receptor for signal transducer and activator of transcription 5 (STAT5) a and b and for the negative regulators of cytokine signaling cytokine-inducible Src-homology 2 (SH2)-containing protein (CIS) and suppressor of cytokine signaling 2 (SOCS2). Y534, Y566, and Y627 are the major recruitment sites for STAT5. A non-overlapping recruitment pattern is observed for SOCS2 and CIS with positions Y487 and Y595 as major binding sites, ruling out SOCS-mediated inhibition of STAT5 activation by competition for shared binding sites. More detailed analysis revealed that CIS binding to the Y595, but not to the Y487 motif, depends on both its SH2 domain and the C-terminal part of its SOCS box, with a critical role for the CIS Y253 residue. This functional divergence of the two CIS/SOCS2 recruitment sites is also observed upon substitution of the Y+1 residue by leucine, turning the Y487, but not the Y595 motif into a functional STAT5 recruitment site.
Direct Binding and Activation of Protein Kinase C Isoforms by Aldosterone and 17β-Estradiol
Authors: Alzamora Rodrigo , Brown Laura R. , Harvey Brian J.
Published: August 2007

Protein kinase C (PKC) is a signal transduction protein that has been proposed to mediate rapid responses to steroid hormones. Previously, we have shown aldosterone directly activates PKCα whereas 17β-estradiol activates PKCα and PKCδ; however, neither the binding to PKCs nor the mechanism of action has been established. To determine the domains of PKCα and PKCδ involved in binding of aldosterone and 17β-estradiol, glutathione S-transferase fusion recombinant PKCα and PKCδ mutants were used to perform in vitro binding assays with [3H]aldosterone and [3H]17β-estradiol. 17β-Estradiol bound both PKCα and PKCδ but failed to bind PKC mutants lacking a C2 domain. Similarly, aldosterone bound only PKCα and mutants containing C2 domains. Thus, the C2 domain is critical for binding of these hormones. Binding affinities for aldosterone and 17β-estradiol were between 0.5–1.0 nM. Aldosterone and 17β-estradiol competed for binding to PKCα, suggesting they share the same binding site. Phorbol 12,13-dybutyrate did not compete with hormone binding; furthermore, they have an additive effect on PKC activity. EC50 for activation of PKCα and PKCδ by aldosterone and 17β-estradiol was approximately 0.5 nM. Immunoblot analysis using a phospho-PKC antibody revealed that upon binding, PKCα and PKCδ undergo autophosphorylation with an EC50 in the 0.5–1.0 nm range. 17β-Estradiol activated PKCα and PKCδ in estrogen receptor-positive and -negative breast cancer cells (MCF-7 and HCC-38, respectively), suggesting estrogen receptor expression is not required for 17β-estradiol-induced PKC activation. The present results provide first evidence for direct binding and activation of PKCα and PKCδ by steroid hormones and the molecular mechanisms involved.
SRY and the Standoff in Sex Determination
Authors: DiNapoli Leo , Capel Blanche
Published: August 2007

SRY was identified as the mammalian sex-determining gene more than 15 yr ago and has been extensively studied since. Although many of the pathways regulating sexual differentiation have been elucidated, direct downstream targets of SRY are still unclear, making a top down approach difficult. However, recent work has demonstrated that the fate of the gonad is actively contested by both male-promoting and female-promoting signals. Sox9 and Fgf9 push gonads towards testis differentiation. These two genes are opposed by Wnt4, and possibly RSPO1, which push gonads toward ovary differentiation. In this review, we will discuss the history of the field, current findings, and exciting new directions in vertebrate sex determination.
Shroom2, a myosin-VIIa- and actin-binding protein, directly interacts with ZO-1 at tight junctions
Authors: Etournay Raphaël , Zwaenepoel Ingrid , Perfettini Isabelle , Legrain Pierre , Petit Christine , El-Amraoui Aziz
Published: August 2007

Defects in myosin VIIa lead to developmental anomalies of the auditory and visual sensory cells. We sought proteins interacting with the myosin VIIa tail by using the yeast two-hybrid system. Here, we report on shroom2, a submembranous PDZ domain-containing protein that is associated with the tight junctions in multiple embryonic and adult epithelia. Shroom2 directly interacts with the C-terminal MyTH4-FERM domain of myosin VIIa and with F-actin. In addition, a shroom2 fragment containing the region of interaction with F-actin was able to protect actin filaments from cytochalasin-D-induced disruption in MDCK cells. Transfection experiments in MDCK and LE (L fibroblasts that express E-cadherin) cells led us to conclude that shroom2 is targeted to the cell-cell junctions in the presence of tight junctions only. In Ca2+-switch experiments on MDCK cells, ZO-1 (also known as TJP1) preceded GFP-tagged shroom2 at the differentiating tight junctions. ZO-1 directly interacts with the serine- and proline-rich region of shroom2 in vitro. Moreover, the two proteins colocalize in vivo at mature tight junctions, and could be coimmunoprecipitated from brain and cochlear extracts. We suggest that shroom2 and ZO-1 form a tight-junction-associated scaffolding complex, possibly linked to myosin VIIa, that bridges the junctional membrane to the underlying cytoskeleton, thereby contributing to the stabilization of these junctions.
Brg1 chromatin remodeling factor is involved in cell growth arrest, apoptosis and senescence of rat mesenchymal stem cells
Authors: Napolitano Marco A. , Cipollaro Marilena , Cascino Antonino , Melone Mariarosa A. B. , Giordano Antonio , Galderisi Umberto
Published: August 2007

Self-renewal, proliferation and differentiation properties of stem cells are controlled by key transcription factors. However, their activity is modulated by chromatin remodeling factors that operate at the highest hierarchical level. Studies on these factors can be especially important to dissect molecular pathways governing the biology of stem cells. SWI/SNF complexes are adenosine triphosphate (ATP)-dependent chromatin remodeling enzymes that have been shown to be required for cell cycle control, apoptosis and cell differentiation in several biological systems. The aim of our research was to investigate the role of these complexes in the biology of mesenchymal stem cells (MSCs). To this end, in MSCs we caused a forced expression of the ATPase subunit of SWI/SNF (Brg1 – also known as Smarca4) by adenoviral transduction. Forced Brg1 expression induced a significant cell cycle arrest of MSCs in culture. This was associated with a huge increase in apoptosis that reached a peak 3 days after transduction. In addition, we observed signs of senescence in cells having ectopic Brg1 expression. At the molecular level these phenomena were associated with activation of Rb- and p53-related pathways. Inhibition of either p53 or Rb with E1A mutated proteins allowed us to hypothesize that both Rb and p53 are indispensable for Brg1-induced senescence, whereas only p53 seems to play a role in triggering programmed cell death. We also looked at the effects of forced Brg1 expression on canonical MSC differentiation in adipocytes, chondrocytes and osteocytes. Brg1 did not induce cell differentiation per se; however, this protein could contribute, at least in part, to the adipocyte differentiation process.

In conclusion, our results suggest that whereas some ATP-dependent chromatin remodeling factors, such as ISWI complexes, promote stem cell self-renewal and conservation of an uncommitted state, others cause an escape from `stemness' and induction of differentiation along with senescence and cell death phenomena.
ZYG-9, TAC-1 and ZYG-8 together ensure correct microtubule function throughout the cell cycle of C. elegans embryos
Authors: Bellanger Jean-Michel , Carter J. Clayton , Phillips Jennifer B. , Canard Coralie , Bowerman Bruce , Gönczy Pierre
Published: August 2007

The early Caenorhabditis elegans embryo is well suited for investigating microtubule-dependent cell division processes. In the one-cell stage, the XMAP215 homologue ZYG-9, associated with the TACC protein TAC-1, promotes microtubule growth during interphase and mitosis, whereas the doublecortin domain protein ZYG-8 is required for anaphase spindle positioning. How ZYG-9, TAC-1 and ZYG-8 together ensure correct microtubule-dependent processes throughout the cell cycle is not fully understood. Here, we identify new temperature-sensitive alleles of zyg-9 and tac-1. Analysis of ZYG-9 and TAC-1 distribution in these mutants identifies amino acids important for centrosomal targeting and for stability of the two proteins. This analysis also reveals that TAC-1 is needed for correct ZYG-9 centrosomal enrichment. Moreover, we find that ZYG-9, but not TAC-1, is limiting for microtubule-dependent processes in one-cell-stage embryos. Using two of these alleles to rapidly inactivate ZYG-9-TAC-1 function, we establish that this complex is required for correct anaphase spindle positioning. Furthermore, we uncover that ZYG-9-TAC-1 and ZYG-8 function together during meiosis, interphase and mitosis. We also find that TAC-1 physically interacts with ZYG-8 through its doublecortin domain, and that in vivo TAC-1 and ZYG-8 are part of a complex that does not contain ZYG-9. Taken together, these findings indicate that ZYG-9-TAC-1 and ZYG-8 act in a partially redundant manner to ensure correct microtubule assembly throughout the cell cycle of early C. elegans embryos.
The tail-anchoring domain of Bfl1 and HCCS1 targets mitochondrial membrane permeability to induce apoptosis
Authors: Ko Jae-Kyun , Choi Kyoung-Han , Pan Zui , Lin Peihui , Weisleder Noah , Kim Chul-Woo , Ma Jianjie
Published: August 2007

Many Bcl2 family proteins target intracellular membranes by their C-terminal tail-anchor domain. Bfl1 is a bi-functional Bcl2 family protein with both anti- and pro-apoptotic activities and contains an amphipathic tail-anchoring peptide (ATAP; residues 147-175) with unique properties. Here we show that ATAP targets specifically to mitochondria, and induces caspase-dependent apoptosis that does not require Bax or Bak. Mutagenesis studies revealed that lysine residues flanking the ATAP sequence are involved in targeting of the peptide to the mitochondrial membrane, and charged residues that contribute to the amphipathic nature of ATAP are critical for its pro-apoptotic function. The ATAP sequence is present in another tumor suppressor gene, HCCS1, which contains an additional mitochondria-targeting signal (MTS) close to the ATAP. We propose that both ATAP and MTS could be used as therapeutic peptides to induce cell death in the treatment of cancer cells.
The fatty acid elongase NOA is necessary for viability and has a somatic role inDrosophilasperm development
Authors: Jung Anita , Hollmann Martin , Schäfer Mireille A.
Published: August 2007

The essential gene noa (CG 3971; also known as Baldspot) encodes a very long chain fatty acid elongase which is most similar to the mammalian elongase ELOVL6. noa is expressed in the nervous system from embryogenesis on, in imaginal discs, the fat body, malpighian tubules and in the gonads of both sexes. Its function is dose dependent, since reduced levels of noa RNA lead to impaired motility and severely reduced viability. In testes, noa RNA is detected in the cyst cells during the postmeiotic phase of germ cell development. An RNAi construct selectively driven in cyst cells leads to male sterility, demonstrating the necessity of noa function for male germline development and the interaction of the somatic cyst cells with the developing sperm.
NSF- and SNARE-mediated membrane fusion is required for nuclear envelope formation and completion of nuclear pore complex assembly in Xenopus laevis egg extracts
Authors: Baur Tina , Ramadan Kristijan , Schlundt Andreas , Kartenbeck Jürgen , Meyer Hemmo H.
Published: August 2007

Despite the progress in understanding nuclear envelope (NE) reformation after mitosis, it has remained unclear what drives the required membrane fusion and how exactly this is coordinated with nuclear pore complex (NPC) assembly. Here, we show that, like other intracellular fusion reactions, NE fusion in Xenopus laevis egg extracts is mediated by SNARE proteins that require activation by NSF. Antibodies against Xenopus NSF, depletion of NSF or the dominant-negative NSFE329Q variant specifically inhibited NE formation. Staging experiments further revealed that NSF was required until sealing of the envelope was completed. Moreover, excess exogenous α-SNAP that blocks SNARE function prevented membrane fusion and caused accumulation of non-flattened vesicles on the chromatin surface. Under these conditions, the nucleoporins Nup107 and gp210 were fully recruited, whereas assembly of FxFG-repeat-containing nucleoporins was blocked. Together, we define NSF- and SNARE-mediated membrane fusion events as essential steps during NE formation downstream of Nup107 recruitment, and upstream of membrane flattening and completion of NPC assembly.
Syntenin mediates Delta1-induced cohesiveness of epidermal stem cells in culture
Authors: Estrach Soline , Legg James , Watt Fiona M.
Published: August 2007

In human interfollicular epidermis, stem cell clusters express high levels of the Notch ligand Delta1. Delta1 stimulates neighbouring cells to differentiate and also promotes stem cell clustering. Although Notch signalling is known to stimulate epidermal differentiation, little is known about the mechanism by which Delta1 promotes epidermal cell cohesiveness. This is an important issue, because the location of stem cells determines the local microenvironmental signals they receive. We now show that mutation of the Delta1 PDZ-binding domain abolishes Delta1-mediated keratinocyte cohesiveness, stimulates Notch transcriptional activity and promotes epidermal differentiation. A yeast two-hybrid screen revealed that Delta1 binds to the adaptor protein syntenin – an interaction dependent on the Delta1 PDZ-binding domain. Syntenin, like Delta1, is upregulated in the stem cell clusters of human interfollicular epidermis. Knockdown of syntenin in cells overexpressing full-length Delta1 had the same effects on Notch signalling, epidermal differentiation and adhesion as overexpressing Delta1 with a mutated PDZ-binding domain. Syntenin has previously been reported to regulate membrane traffic, and mutation of the Delta1 PDZ-binding domain or knockdown of syntenin led to rapid internalisation of Delta1. We propose that syntenin binding to Delta1 plays a dual role in promoting intercellular adhesion and regulating Notch signalling.
Preparation of Calcium Silicate Nanobelts and the In Vitro Behavior in a Simulated Body Fluid
Authors: Ling Huiqin , Liu Qun , Chang Chengkang , Mao Dali
Published: July 2007

Single-crystalline CaSiO3 nanobelts were prepared via a simple solvothermal routine. The synthesized material revealed bioactive response when immersed in a simulated body fluid (SBF) solution, suggesting its potential application as biomedical materials.
TTF–Cytosine Dyad as an Electron-donor Molecule Having Proton-accepting Ability: Formation of Hemiprotonated Cytosine Dimer in I3− Salt
Authors: Miyazaki Eigo , Morita Yasushi , Yakiyama Yumi , Maki Suguru , Umemoto Yoshikazu , Ohmoto Makoto , Nakasuji Kazuhiro
Published: July 2007

A tetrathiafulvalene (TTF) derivative with a cytosine moiety was designed and synthesized as a bi-functional molecule with both electron-donating and proton-accepting abilities. In the crystal of I3− salt, TTF–cytosine dyad formed a hemiprotonated dimer through triple hydrogen-bonds with radical cationic state of the TTF moieties.