bluuebunny/crossref_metadata_2025 huggingface dataset:
Bovine and human cathelicidin cationic host defense peptides similarly suppress transcriptional responses to bacterial lipopolysaccharide
Authors: Mookherjee Neeloffer , Wilson Heather L , Doria Silvana , Popowych Yurij , Falsafi Reza , Yu Jie (Jessie) , Li YueXin , Veatch Sarah , Roche Fiona M , Brown Kelly L , Brinkman Fiona S L , Hokamp Karsten , Potter Andy , Babiuk Lorne A , Griebel Philip J , Hancock Robert E W
Published: August 2006

Genomic approaches can be exploited to expose the complexities and conservation of biological systems such as the immune network across various mammalian species. In this study, temporal transcriptional expression profiles were analyzed in human and bovine monocytic cells in response to the TLR-4 agonist, LPS, in the presence or absence of their respective host defense peptides. The cathelicidin peptides, human LL-37 and bovine myeloid antimicrobial peptide-27 (BMAP-27), are homologs, yet they have diverged notably in terms of sequence similarity. In spite of their low sequence similarities, both of these cathelicidin peptides demonstrated potent, antiendotoxin activity in monocytic cells at low, physiologically relevant concentrations. Microarray studies indicated that 10 ng/ml LPS led to the up-regulation of 125 genes in human monocytes, 106 of which were suppressed in the presence of 5 μg/ml of the human peptide LL-37. To confirm and extend these data, temporal transcriptional responses to LPS were assessed in the presence or absence of the species-specific host defense peptides by quantitative real-time PCR. The transcriptional trends of 20 LPS-induced genes were analyzed in bovine and human monocytic cells. These studies demonstrated conserved trends of gene responses in that both peptides were able to profoundly suppress many LPS-induced genes. Consistent with this, the human and bovine peptides suppressed LPS-induced translocation of NF-κB subunits p50 and p65 into the nucleus of monocytic cells. However, there were also distinct differences in responses to LPS and the peptides; for example, treatment with 5 μg/ml BMAP-27 alone tended to influence gene expression (RELA, TNF-α-induced protein 2, MAPK phosphatase 1/dual specificity phosphatase 1, IκBκB, NFκBIL1, TNF receptor-associated factor 2) to a greater extent than did the same amount of human LL-37. We hypothesize that the immunomodulatory effects of the species-specific host defense peptides play a critical role in regulating inflammation and represent an evolutionarily conserved mechanism for maintaining homeostasis, although the sequence divergence of these peptides is substantial.
GRKs and arrestins: regulators of migration and inflammation
Authors: Vroon Anne , Heijnen Cobi J , Kavelaars Annemieke
Published: August 2006

In the immune system, signaling by G protein-coupled receptors (GPCRs) is crucial for the activity of multiple mediators, including chemokines, leukotrienes, and neurotransmitters. GPCR kinases (GRKs) and arrestins control GPCR signaling by mediating desensitization and thus, regulating further signal propagation through G proteins. Recent evidence suggests that the GRK-arrestin desensitization machinery fulfills a vital role in regulating inflammatory processes. First, GRK/arrestin levels in immune cells are dynamically regulated in response to inflammation. Second, in animals with targeted deletion of GRKs or arrestins, the progression of various acute and chronic inflammatory disorders, including autoimmunity and allergy, is profoundly affected. Third, chemokine receptor signaling in vitro is known to be tightly regulated by the GRK/arrestin machinery, and even small changes in GRK/arrestin expression can have a marked effect on cellular responses to chemokines. This review integrates data about the role of GRKs and arrestins in inflammation, with results on the molecular mechanism of action of GRKs/arrestins, and describes the pivotal role of GRKs/arrestins in inflammatory processes, with a special emphasis on regulation of chemokine responsiveness.
All in the mind? The neural correlates of unexplained physical symptoms
Authors: Spence Sean A.
Published: August 2006

Physical symptoms with no medical explanation are commonly experienced by healthy people and those attending clinics. Psychiatrists see such patients in liaison settings and clinics for those with psychotic and affective disorders. The pathophysiology remains obscure; physical investigations are usually performed to exclude pathology rather than elucidate dysfunction. However, modern neuroimaging has allowed the study of nervous system structure and function. Although there are few diagnostically specific findings, patterns of association have emerged: where action is impeded (certain forms of conversion disorder and chronic fatigue syndrome) frontal systems of the brain are often implicated; when subjective awareness of the body is disturbed (passivity phenomena and anorexia nervosa) temporo-parietal cortices appear to be dysfunctional. The caudate nuclei (components of the frontal executive circuit) are implicated in a variety of syndromes (including body dysmorphic disorder, somatisation and chronic fatigue). The brain may be viewed as a cognitive neurobiological entity, crucially oriented towards action (for survival). Psychiatric syndromes that have an impact on bodily awareness signal dysfunction within systems representing that body and its performance in time and space.
Computers, the internet and the World Wide Web: an introduction for the e-therapist
Authors: Tantam Digby
Published: August 2006

The purpose of this first article of four addressing the electronic approaches to psychotherapy (e-therapy) is to introduce the equipment (computers) and systems (the World Wide Web and the internet) involved. I describe some of their many elements (e.g. bits and bytes), uses (such as search engines, email, web mail) and a few abuses (e.g. spam, spyware).
Opportunities and risks in e-therapy
Authors: Tantam Digby
Published: August 2006

The world wide web has many advantages for the psychotherapist and for the client, but it poses new challenges too. This article considers both in relation to information, disinformation and information overload; openness and availability of information; and the anomalies of being present, and able to meet other presences, in virtual space but with no physical body and with an identity that may be created for the occasion.
Screening for illicit drug use in psychiatric hospitals: whose job is it?
Authors: Crome Ilana B. , Bloor Roger , Thom Betsy
Published: August 2006

This review focuses on screening and assessment in general psychiatric settings, where drug use is unlikely to be known to service providers. It builds on the recurrent finding that psychiatric patients are at high risk of substance misuse. The application of self-report questionnaires and rating scales and more in-depth assessment instruments is outlined, as are biological screening techniques. The use of brief self-completion questionnaires probably offers the most practical approach to routine screening by non-specialist staff in general hospital settings. The importance of implementing such tools lies in reaching an accurate diagnosis, choosing treatments more appropriately and monitoring the management of patients' psychiatric disorders.
Strategies for discontinuing long-term benzodiazepine
use
Authors: Voshaar Richard C. Oude , Couvée Jaap E. , Van Balkom Anton J. L. M. , Mulder Paul G. H. , Zitman Frans G.
Published: August 2006

Background

The prevalence of benzodiazepine consumption in European countries
remains at 2–3% of the general population despite the well-documented
disadvantages of long-term use.

Aims

To review systematically the success rates of different benzodiazepine
discontinuation strategies.

Method

Meta-analysis of comparable intervention studies.

Results

Twenty-nine articles met inclusion criteria. Two groups of interventions
were identified; minimal intervention (e.g. giving simple advice in the
form of a letter or meeting to a large group of people;
n=3), and systematic discontinuation (defined as
treatment programmes led by a physician or psychologist;
n=26). Both were found to be significantly more
effective than treatment as usual: minimal interventions (pooled OR=2.8,
95% CI 1.6–5.1); systematic discontinuation alone (one study, OR=6.1, 95%
CI 2.0–18.6). Augmentation of systematic discontinuation with imipramine
(two studies, OR=3.1, 95% CI 1.1–9.4) or group cognitive-behavioural
therapy for patients with insomnia (two studies, OR=5.5, 95% CI 2.3–14.2)
was superior to systematic discontinuation alone.

Conclusions

Evidence was found for the efficacy of stepped care (minimal intervention
followed by systematic discontinuation alone) in discontinuing long-term
benzodiazepine use.
Relationship between disabling fatigue and depression in children
Authors: Fowler Tom A. , Rice Frances , Thapar Anita , Farmer Anne
Published: August 2006

Background

Medically unexplained disabling fatigue in young people is familial and frequently associated with depressed mood.

Aims

To examine the degree of sharing of genetic and environmental influences on the symptoms of depression and fatigue in this age group.

Method

The parents of twins aged 8–17 years, derived from a population-based register, completed a questionnaire regarding lifetime-ever disabling fatigue in both twins. Twins aged 11 years or over completed the Mood and Feelings Questionnaire. The genetic and environmental influences on fatigue and the relationship with depression were examined using bivariate genetic analysis.

Results

Parent-rated data were obtained for 1468 twin pairs (65%) and self-rated data from 930 older twin pairs (58%). Bivariate analysis of fatigue and depression suggested that genetic and environmental influences on disabling fatigue were mainly specific to fatigue.

Conclusions

Unexplained disabling fatigue in childhood is substantially familial and has mainly an independent aetiology from depression.
Outcome of major depression in Ethiopia
Authors: Mogga Souci , Prince Martin , Alem Atalay , Kebede Derege , Stewart Robert , Glozier Nick , Hotopf Matthew
Published: August 2006

Background

The outcome and impact of major depression in developing countries are
not clear.

Aims

To describe the outcome of major depression and compare the disability
and patterns of service use among different outcome groups.

Method

In a case cohort study, nested within a population-based survey of 68 000
participants using the Composite International Diagnostic Interview
(CIDI), 300 participants were randomly selected from those with current
major depression and 300 from those with no lifetime history.
Participants were re-interviewed after 18–62 months to ascertain current
diagnosis, psychological symptoms, disability and use of health
services.

Results

Of participants with major depression at baseline 26% also met criteria
for major depression at follow up. Mortality ratio standardised for age
and gender was 3.55 (95% CI 1.97 to 6.39). All indices of measure of
disability were significantly higher in the persistently depressed group
compared with the completely recovered group. Participants who had
recovered partially resembled participants with persistent depression.
Two-thirds of those with persistent depression had not sought any
help.

Conclusions

Major depression was associated with mortality and disability Those with
residual symptoms remained disabled. Help-seeking was unusual.
Cerebral emboli and depressive symptoms in
dementia
Authors: Purandare Nitin , Voshaar Richard C. Oude , Hardicre Jayne , Byrne Jane , McCollum Charles , Burns Alistair
Published: August 2006

Background

The vascular depression hypothesis and our recent findings of increased
frequency of spontaneous cerebral emboli in dementia suggest that such
emboli may be involved in the causation of depressive symptoms in
dementia.

Aims

To evaluate the association between spontaneous cerebral emboli and
depressive symptoms in Alzheimer's disease and vascular dementia.

Method

In a cohort of 142 patients with dementia (72 with Alzheimer's disease
and 70 with vascular dementia), the association between spontaneous
cerebral emboli and clinically relevant depressive symptoms was examined
using multiple logistic regression analyses.

Results

Spontaneous cerebral emboli were significantly more frequent in the
patients with clinically relevant depressive symptoms (66
v. 37%, P=0.03). After adjustment
for age, gender, Mini-Mental State Examination score, type of dementia
and significant cardiovascular risk factors, the relationship remained
significant (OR=3.47, 95% CI 1.10–10.97).

Conclusions

Spontaneous cerebral emboli are associated with clinically relevant
depressive symptoms in dementia, and further research is needed to
explore the nature of this relationship.
Substance misuse in first-episode psychosis: 15-month
prospective follow-up study
Authors: Wade D. , Harrigan S. , Edwards J. , Burgess P. M. , Whelan G. , McGorry P. D.
Published: August 2006

Background

Well-designed prospective studies of substance misuse in first-episode
psychosis can improve our understanding of the risks associated with
comorbid substance misuse and psychosis.

Aims

To examine the potential effects of substance misuse on in-patient
admission and remission and relapse of positive symptoms in first-episode
psychosis.

Method

The study was a prospective 15-month follow-up investigation of 103
patients with first-episode psychosis recruited from three mental health
services.

Results

Substance misuse was independently associated with increased risk of
in-patient admission, relapse of positive symptoms and shorter time to
relapse of positive symptoms after controlling for potential confounding
factors. Substance misuse was not associated with remission or time to
remission of positive symptoms. Heavy substance misuse was associated
with increased risk of in-patient admission, relapse and shorter time to
relapse.

Conclusions

Substance misuse is an independent risk factor for a problematic recovery
from first-episode psychosis.
Deaths from pesticide poisoning: a global response
Authors: Bertolote J. M. , Fleischmann A. , Eddleston M. , Gunnell D.
Published: August 2006

Self-poisoning with pesticides accounts for about a third of all suicides worldwide. To tackle this problem, the World Health Organization announced a global public health initiative in the second half of 2005. Planned approaches were to range from government regulatory action to the development of new treatments for pesticide poisoning. With broad-based support, this strategy should have a major impact on the global burden of suicide.
Evaluating the effectiveness of a women's crisis house: a prospective observational study
Authors: Meiser-Stedman Caroline , Howard Louise , Cutting Penny
Published: August 2006

Aims and Method

To investigate the effectiveness of the Women's Service crisis house in Croydon we performed an observational study prospectively measuring functioning, symptom severity and unmet needs before and after admission. Use of mainstream mental health services was also measured.

Results

Women using the service had high use of mainstream mental health services, with 137 out of 269 (51%) requiring admission to a mainstream acute ward in the 4 years studied. The service was effective with an improvement in Global Assessment of Functioning scores from a median of 48 on admission to 67 on discharge (P<0.001).

Clinical Implications

The women's crisis house was effective in providing for women who required high levels of mainstream mental health services, suggesting that it provides a valuable alternative to standard in-patient care.
Setting up a methadone maintenance clinic in a hostel in London's West End
Authors: Dunn John , Robertson David , Davis Paul , Khosrawan Babak , Christian Suneel
Published: August 2006

Aims and Method

A satellite methadone prescribing service was set up in a hostel in London's West End. The aim was to investigate if it were feasible to engage and retain these hard-to-reach, chaotic, polydrug users in treatment. A basic needs assessment was undertaken with staff and clients at the hostel. Treatment outcomes were assessed at 16 weeks using the Maudsley Addiction Profile.

Results

At 16 weeks 87% of the original cohort (26 out of 30) were still in treatment. There were also significant reductions in mean heroin use (from 29.7 to 14.5 out of the past 30 days, P<0.001) and in the frequency of injecting (from 25.9 to 15.9 days, P<0.001).

Clinical Implications

This outreach clinic offers a model for developing services to homeless people with substance misuse problems.
Psychological formulations in psychiatric care: staff views on their impact
Authors: Summers Alison
Published: August 2006

Aims and Method

To understand the benefits and limitations of using psychological formulations for patients with severe mental illness, a qualitative study of staff views was conducted, based on semi-structured interviews with 25 staff working in a high-dependency rehabilitation service.

Results

Participants believed that formulations benefited care planning, staff–patient relationships, staff satisfaction and teamworking, through increasing understanding of patients, bringing together staff with different views and encouraging more creative thinking. They particularly valued meeting together to develop the formulations. Some staff accepted formulations as tentative and provisional, whereas others regarded them as statements of conviction.

Clinical Implications

The study suggests that using psychological formulations in the care of psychiatric patients may well be valuable, but needs further exploration.
Psychiatry: no longer in dissent?
Authors: Kelly Brendan D. , Feeney Larkin
Published: August 2006

Medicine thrives on dissent. Of all the medical disciplines, psychiatry seems to generate the highest level of dissent, both from inside and outside the profession: no other medical discipline, for example, has some of its own members consistently argue that its very foundations are rooted in a series of harmful myths (Szasz, 1974, 2003). The best responses to this type of criticism identify the core concerns of the critic, dissect out the most relevant arguments and develop ways to integrate useful suggestions with existing knowledge, so as to advance the field in a pragmatic, sensible and evidence-based fashion. Such constructive responses to controversy are rare.
Outpatient Oral Antibiotics for Febrile Neutropenic Cancer Patients Using a Score Predictive for Complications
Authors: Klastersky Jean , Paesmans Marianne , Georgala Aspasia , Muanza Frédérique , Plehiers Barbara , Dubreucq Laurent , Lalami Yassine , Aoun Michel , Barette Martine
Published: August 2006

Purpose

Since febrile neutropenic patients were recognized to constitute a heterogeneous population, several models have been developed for predicting the risk of serious medical complications. The Multinational Association for Supportive Care in Cancer score and its derived clinical prediction rules have been validated, but thus far there were no data about its use for simplifying therapy in predicted low-risk patients.

Patients and Methods

In a single institution, we followed all episodes of febrile neutropenia between January 1999 and November 2003. Those patients predicted at low risk for complications, who were not receiving antibacterials at fever onset and were eligible for treatment with oral antibiotics, were treated with ciprofloxacin and amoxicillin-clavulanate and were discharged if they were clinically stable or improving after an initial observation period. The primary end point of the study was the rate of resolution of the febrile neutropenic episode without complications, among these early discharged patients.

Results

Of 383 first febrile neutropenic episodes predicted at low risk of omplication, 178 patients (33 men and 145 women, mainly with solid tumors) were treated orally; they constituted the basis of our analysis. Seventy-nine patients (44%) were discharged early (with a median time to discharge of 26 hours); no complications occurred among them but three patients had to be readmitted, resulting in a success rate of 96% (95% CI, 92% to 100%).

Conclusion

Our study shows that oral therapy followed by early discharge was feasible in a small but significant proportion of patients selected by a strategy combining predicted low risk and medical and nonmedical criteria.
Thymidine Phosphorylase Expression Is Associated With Response to Capecitabine Plus Irinotecan in Patients With Metastatic Colorectal Cancer
Authors: Meropol Neal J. , Gold Philip J. , Diasio Robert B. , Andria Michael , Dhami Mandeep , Godfrey Thomas , Kovatich Albert J. , Lund Kirk A. , Mitchell Edith , Schwarting Roland
Published: August 2006

Purpose

To evaluate the clinical activity and toxicity of capecitabine plus irinotecan as first-line therapy for patients with metastatic colorectal cancer (mCRC), and to describe the association of expression of thymidine phosphorylase (TP), thymidylate synthase (TS), and dihydropyrimidine dehydrogenase (DPD) with antitumor activity.

Patients and Methods

Patients with previously untreated mCRC received irinotecan days 1 and 8 intravenously, and capecitabine days 2 to 15 orally in 21-day cycles. Doses were irinotecan 125 mg/m2and capecitabine 1,000 mg/m2bid (n = 15; cohort 1), or irinotecan 100 mg/m2and capecitabine 900 mg/m2bid (n = 52; cohort 2). Tissues from primary and metastatic sites were assessed for TP, TS, and DPD gene and protein expression.

Results

An unacceptable level of GI toxicity in the first 15 patients led to a protocol modification in starting doses. The response rate was 45% (30 of 67 patients). Overall survival was associated with TP expression assessed by immunohistochemistry in both primary tumors (P = .045) and metastases (P = .001). Objective tumor response was associated with TP expression in primary tumors (odds ratio, 4.77; 95% CI, 1.25 to 18.18), with a similar trend in metastases (odds ratio, 8.67; 95% CI, 0.95 to 79.1). TP gene expression in primary tumors was also associated with response.

Conclusion

These data indicate that capecitabine plus irinotecan is an active regimen against mCRC. The biomarker analysis (including metastatic tissue) was feasible in a multicenter setting, and provides preliminary evidence that TP expression may be a predictive marker for response.
Phase I Dose Escalation and Pharmacokinetic Study of Enzastaurin, an Oral Protein Kinase C Beta Inhibitor, in Patients With Advanced Cancer
Authors: Carducci Michael A. , Musib Luna , Kies Merrill S. , Pili Roberto , Truong Mylene , Brahmer Julie R. , Cole Patricia , Sullivan Rana , Riddle Jeanne , Schmidt Jill , Enas Nathan , Sinha Vikram , Thornton Donald E. , Herbst Roy S.
Published: August 2006

Purpose

This phase I study was conducted to determine the recommended dose of enzastaurin, an oral protein kinase C beta (PKCβ) inhibitor, for phase II trials. Secondary objectives were maximum-tolerated dose (MTD), pharmacokinetics (PK), toxicity, and response.

Patients and Methods

Patients at least 18 years of age with advanced cancer and an Eastern Cooperative Oncology Group performance status of 0 or 1 lower received enzastaurin orally once daily at a starting dose of 20 mg. Dose escalation proceeded using a modified Simon design.

Results

All 47 patients enrolled (mean age, 58 years) received at least one dose of enzastaurin, with a median of two cycles (range, one to 17 cycles). Prevalent malignancies were lung (n = 10) and head and neck cancers (n = 9). Although no MTD was identified up to 700 mg/d, 525 mg was chosen as the recommended dose, and 12 additional patients were accrued at that level. Three dose-limiting toxicities (QTc changes) occurred: one at the 700-mg dose (patient discontinued), and two in the expansion cohort at the 525-mg dose. Total analytes (enzastaurin and its metabolites) exposure increased with increasing doses up to 240 mg, and appeared to plateau at 525 and 700 mg. Grade 1 chromaturia, fatigue, and other GI toxicities were the most common, while no clinically significant grade 3/4 toxicities occurred. Two deaths, unrelated to enzastaurin, occurred. Twenty-one patients (45%) achieved stable disease (SD) for two to 16 cycles.

Conclusion

On the basis of plasma exposures and safety data, enzastaurin 525 mg once daily is the recommended phase II dose. Enzastaurin is well tolerated up to 700 mg/d. Evidence of early activity was seen with significant stable disease.
Prognostic Impact of Germinal Center–Associated Proteins and Chromosomal Breakpoints in Poor-Risk Diffuse Large B-Cell Lymphoma
Authors: van Imhoff Gustaaf W. , Boerma Evert-Jan G. , van der Holt Bronno , Schuuring Ed , Verdonck Leo F. , Kluin-Nelemans Hanneke C. , Kluin Philip M.
Published: August 2006

Purpose

Outcome of diffuse large B-cell lymphoma (DLBCL) with a germinal center B-cell (GCB) expression profile is superior to that of non-GCB DLBCL. This conclusion is mainly derived from patients with mixed international prognostic index (IPI) risk profiles treated with CHOP-like therapy (cyclophosphamide, doxorubicin, vincristine, and prednisone). We wondered whether the prognostic impact of the expression profile would hold out in a homogeneous cohort of poor-risk DLBCL patients treated with high-dose sequential therapy (HDT) and autologous stem-cell transplantation (ASCT) as first-line therapy.

Patients and Methods

DLBCL from 66 newly diagnosed poor-risk patients, treated in two sequential prospective Dutch Hemato-Oncology Association (HOVON) trials, were studied retrospectively for expression of CD10, bcl6, MUM1/IRF4, bcl2, Ki67, and CD21+ follicular dendritic cells (FDC) by immunohistochemistry, and for the breakpoints of BCL2, BCL6, and MYC by fluorescent in situ hybridization (FISH). Lymphomas with any follicular component were excluded.

Results

A GCB immunophenotype profile was found in 58% and non-GCB immunophenotype profile in 42% of the tumors. Clinical characteristics of both groups were similar. Complete response (CR) rate was higher in patients with CD10+ tumors (58% v 30%; P = .03). A GCB immunophenotype profile, its constituting markers CD10 more than 30% and MUM1 less than 70%, and bcl2 less than 10% were each associated with a better overall survival (OS). FDC networks, equally present in GCB and non-GCB tumors, had superior CR (73% v 31%; P = .01), but disease-free survival rates were lower and there was no difference in OS rates. None of the breakpoints had a prognostic impact on outcome.

Conclusion

Also in patients with poor-risk DLBCL treated with HDT and ASCT, the GCB immunophenotype and bcl2 expression retained a major impact on survival.
Phase I/II Study of Docetaxel, Cisplatin, and Concomitant Boost Radiation for Locally Advanced Squamous Cell Cancer of the Head and Neck
Authors: Tsao Anne S. , Garden Adam S. , Kies Merrill S. , Morrison William , Feng Lei , Lee J. Jack , Khuri Fadlo , Zinner Ralph , Myers Jeffery , Papadimitrakopoulou Vassiliki , Lewin Jan , Clayman Gary L. , Ang K. Kian , Glisson Bonnie S.
Published: August 2006

Purpose

To investigate the feasibility of combining concomitant boost accelerated radiation with docetaxel and cisplatin and assess the regimen's toxicity, locoregional control rate, and survival in patients with locally advanced head and neck cancer (HNSCC).

Patients and Methods

Patients with stage III-IV HNSCC were eligible. Phase I included two schedules of docetaxel and cisplatin: arm 1, once per week during weeks 1 to 4; arm 2, every 21 days for weeks 1 and 4. Radiation consisted of 72 Gy in 42 fractions over 6 weeks (concomitant boost).

Results

Twenty patients were enrolled in phase I. The arm 1 maximum-tolerated dose (MTD) was defined at docetaxel 15 mg/m2 and cisplatin 20 mg/m2 based on prolonged mucositis in 29% of patients. The initial dose level in arm 2 was above the MTD. In total, 52 patients were treated using the arm 1 regimen in phase II. Acute toxicity included grade 3 mucositis and dermatitis in 81% and 44% of patients. The 2-year locoregional control rate was 71%. The 2-year progression-free and overall survival rates were 61% and 65%. Median survival was 37.8 months. Late effects included feeding tube dependence in 17% of patients alive and free of disease.

Conclusion

Locoregional control, survival, and acute toxicity with this regimen were comparable with other trials utilizing taxanes and/or platins and concomitant conventional or altered fractionation radiation. Our data suggest that chemotherapy added to concomitant boost fractionation may increase rates of long-term feeding tube dependence. Phase III trials are needed to assess the contribution of concomitant boost fractionation to chemoradiotherapy.
Impact of a Multi-Disciplinary Patient Education Session on Accrual to a Difficult Clinical Trial: The Toronto Experience With the Surgical Prostatectomy Versus Interstitial Radiation Intervention Trial
Authors: Wallace Kris , Fleshner Neil , Jewett Michael , Basiuk Joan , Crook Juanita
Published: August 2006

Purpose

Random assignment to clinical trials involving different treatment modalities can be difficult. We describe our experience with the Surgical Prostatectomy Versus Interstitial Radiation Intervention Trial (SPIRIT; ACOSOG Z0070 NCIC PR10), a randomized trial for early-stage prostate cancer comparing radical prostatectomy (RP), and brachytherapy (BT). A multidisciplinary educational session was developed to improve patient understanding of treatment options and to facilitate accrual.

Patients and Methods

Prostate cancer referrals were screened and men who met favorable risk criteria (T1c/T2a, prostate-specific antigen [PSA] < 10 ng/mL, Gleason ≤ 6) were invited to a structured education session before a specialty consultation. Men and their partners viewed the SPIRIT informed-consent video and heard from a cancer patient who described his participation in a randomized trial. Then, a urologist and radiation oncologist together compared and contrasted RP and BT to establish the rationale for the trial.

Results

In May 2002, SPIRIT opened for accrual and was endorsed by the University Health Network urologists and radiation oncologists. The first 27 eligible patients were approached about SPIRIT, consulted both specialties, and viewed an educational video. No patients consented. The multidisciplinary education session was then introduced. Forty-seven education sessions with 263 patients resulted in 34 consents. Of 203 patients who were suitable for the study but declined random assignment, 62 chose surgery, 94 chose brachytherapy, three patients chose external radiotherapy, and 11 chose no treatment. Consent rates for eligible and suitable patients were one in six.

Conclusion

Men who understand their treatment options and trial rationale as presented jointly by representative specialists from competing treatment modalities may be better equipped to make an informed decision and are more likely to consent to random assignment.
Phase III Study of Craniospinal Radiation Therapy Followed by Adjuvant Chemotherapy for Newly Diagnosed Average-Risk Medulloblastoma
Authors: Packer Roger J. , Gajjar Amar , Vezina Gilbert , Rorke-Adams Lucy , Burger Peter C. , Robertson Patricia L. , Bayer Lisa , LaFond Deborah , Donahue Bernadine R. , Marymont MaryAnne H. , Muraszko Karin , Langston James , Sposto Richard
Published: August 2006

Purpose

To determine the event-free survival (EFS) and overall survival of children with average-risk medulloblastoma and treated with reduced-dose craniospinal radiotherapy (CSRT) and one of two postradiotherapy chemotherapies.

Methods

Four hundred twenty-one patients between 3 years and 21 years of age with nondisseminated medulloblastoma (MB) were prospectively randomly assigned to treatment with 23.4 Gy of CSRT, 55.8 Gy of posterior fossa RT, plus one of two adjuvant chemotherapy regimens: lomustine (CCNU), cisplatin, and vincristine; or cyclophosphamide, cisplatin, and vincristine.

Results

Forty-two of 421 patients enrolled were excluded from analysis. Sixty-six of the remaining 379 patients had incompletely assessable postoperative studies. Five-year EFS and survival for the cohort of 379 patients was 81% ± 2.1% and 86% ± 9%, respectively (median follow-up over 5 years). EFS was unaffected by sex, race, age, treatment regimen, brainstem involvement, or excessive anaplasia. EFS was detrimentally affected by neuroradiographic unassessability. Patients with areas of frank dissemination had a 5-year EFS of 36% ± 15%. Sixty-seven percent of progressions had some component of dissemination. There were seven second malignancies. Infections occurred more frequently on the cyclophosphamide arm and electrolyte abnormalities were more common on the CCNU regimen.

Conclusion

This study discloses an encouraging EFS rate for children with nondisseminated MB treated with reduced-dose craniospinal radiation and chemotherapy. Additional, careful, step-wise reductions in CSRT in adequately staged patients may be possible.
Six-Month Androgen Suppression Plus Radiation Therapy Compared With Radiation Therapy Alone for Men With Prostate Cancer and a Rapidly Increasing Pretreatment Prostate-Specific Antigen Level
Authors: D'Amico Anthony V. , Loffredo Marian , Renshaw Andrew A. , Loffredo Brittany , Chen Ming-Hui
Published: August 2006

Purpose

We evaluated whether treatment with 6 months of androgen-suppression therapy (AST) and radiation therapy (RT) compared with RT was associated with the time to prostate-specific antigen (PSA) recurrence, prostate cancer–specific mortality (PCSM), and all-cause mortality (ACM) in men with a pretreatment PSA velocity more than 2 ng/mL/yr.

Patients and Methods

The study cohort comprised 241 men with clinically localized or locally advanced prostate cancer treated with RT and AST or RT from 1989 to 2002. Cox regression and Gray's formulation were used to assess whether treatment was associated significantly with the time to PSA recurrence or ACM and PCSM, respectively, adjusting for known prognostic factors.

Results

Despite the significantly longer median follow-up, younger age at diagnosis, higher proportion of Gleason score 7 to 10, and advanced T-category cancers, significantly lower estimates of PSA recurrence (P < .001), PCSM (P = .007), and ACM (P < .001) were observed in men who were treated using RT and AST compared with RT. Treatment with RT and AST compared with RT was associated with a longer time to PSA recurrence (adjusted hazard ratio [HR], 0.22; 95% CI, 0.14 to 0.35; P < .001), PCSM (HR, 0.23, 95% CI, 0.09 to 0.64; P = .005), and ACM (HR, 0.30; 95% CI, 0.16 to 0.58; P < .001).

Conclusion

Treatment using 6 months of AST and RT compared with RT in men with a pretreatment PSA velocity greater than 2 ng/mL/yr was associated with a longer time to PSA recurrence, PCSM, and ACM.
Cost-Effectiveness Analysis of Computerized Tomography in the Routine Follow-Up of Patients After Primary Treatment for Hodgkin’s Disease
Authors: Guadagnolo Beverly A. , Punglia Rinaa S. , Kuntz Karen M. , Mauch Peter M. , Ng Andrea K.
Published: August 2006

Purpose

To estimate the clinical benefits and cost effectiveness of computed tomography (CT) in the follow-up of patients with complete response (CR) after treatment for Hodgkin’s disease (HD).

Patients and Methods

We developed a decision-analytic model to evaluate follow-up strategies for two hypothetical cohorts of 25-year-old patients with stage I-II or stage III-IV HD, treated with doxorubicin, bleomycin, vinblastine, and dacarbazine-based chemotherapy with or without radiation therapy, respectively. We compared three strategies for observing asymptomatic patients after CR: routine annual CT for 10 years, annual CT for 5 years, or follow-up with non-CT modalities only. We used Markov models to calculate life expectancy, quality-adjusted life expectancy, and lifetime costs. Baseline probabilities, transition probabilities, and utilities were derived from published studies. Cost data were derived from the Medicare fee schedule and medical literature. We performed sensitivity analyses by varying baseline estimates.

Results

Annual CT follow-up is associated with minimal survival benefit. With adjustments for quality of life, we found a decrement in quality-adjusted life expectancy for early-stage patients followed with CT compared with non-CT modalities. Sensitivity analyses showed annual CT for 5 years becomes more effective than non-CT follow-up if the specificity of CT is 80% or more or if the disutility associated with a false-positive CT result is less than 0.01 quality-adjusted life years (QALYs). For advanced-stage patients, annual CT for 5 years is associated with a very small quality-adjusted survival gain over non-CT follow-up with an incremental cost-effectiveness ratio of $9,042,300/QALY.

Conclusion

Our analysis suggests that routine CT should not be used in the surveillance of asymptomatic patients in CR after treatment for HD.
Increased Epidermal Growth Factor Receptor Gene Copy Number Is Associated With Poor Prognosis in Head and Neck Squamous Cell Carcinomas
Authors: Chung Christine H. , Ely Kim , McGavran Loris , Varella-Garcia Marileila , Parker Joel , Parker Natalie , Jarrett Carolyn , Carter Jesse , Murphy Barbara A. , Netterville James , Burkey Brian B. , Sinard Robert , Cmelak Anthony , Levy Shawn , Yarbrough Wendell G. , Slebos Robbert J.C. , Hirsch Fred R.
Published: August 2006

Purpose

High epidermal growth factor receptor (EGFR) gene copy number is associated with poor prognosis in lung cancer, but such findings have not been reported for HNSCC. A better understanding of the EGFR pathway may improve the use of EGFR inhibitors in HNSCC.

Patients and Methods

EGFR status was analyzed in 86 tumor samples from 82 HNSCC patients by fluorescent in situ hybridization (FISH) to determine EGFR gene copy number, by polymerase chain reaction and direct sequencing for activating mutations, and by DNA microarray and immunohistochemistry for RNA and protein expression. The results were associated with patient characteristics and clinical end points.

Results

Forty-three (58%) of 75 samples with FISH results demonstrated EGFR high polysomy and/or gene amplification (FISH positive). The FISH-positive group did not differ from the FISH-negative group with respect to age, sex, race, tumor grade, subsites and stage, or EGFR expression by analyses of RNA or protein. No activating EGFR mutations were found. However, the FISH-positive group was associated with worse progression-free and overall survival (P < .05 and P < .01, respectively; log-rank test). When microarray data were interrogated using the FISH results as a supervising parameter, ECop (which is known to coamplify with EGFR and regulate nuclear factor-kappa B transcriptional activity) had higher expression in FISH-positive tumors.

Conclusion

High EGFR gene copy number by FISH is frequent in HNSCC and is a poor prognostic indicator. Additional investigation is indicated to determine the biologic significance and implications for EGFR inhibitor therapies in HNSCC.
Perlecan and Dystroglycan act at the basal side of theDrosophilafollicular epithelium to maintain epithelial organization
Authors: Schneider Martina , Khalil Ashraf A. , Poulton John , Castillejo-Lopez Casimiro , Egger-Adam Diane , Wodarz Andreas , Deng Wu-Min , Baumgartner Stefan
Published: August 2006

Dystroglycan (Dg) is a widely expressed extracellular matrix (ECM) receptor required for muscle viability, synaptogenesis, basementmembrane formation and epithelial development. As an integral component of the Dystrophin-associated glycoprotein complex, Dg plays a central role in linking the ECM and the cytoskeleton. Disruption of this linkage in skeletal muscle leads to various types of muscular dystrophies. In epithelial cells, reduced expression of Dg is associated with increased invasiveness of cancer cells. We have previously shown that Dg is required for epithelial cell polarity in Drosophila,but the mechanisms of this polarizing activity and upstream/downstream components are largely unknown. Using the Drosophila follicle-cell epithelium (FCE) as a model system, we show that the ECM molecule Perlecan(Pcan) is required for maintenance of epithelial-cell polarity. Follicle cells that lack Pcan develop polarity defects similar to those of Dg mutant cells. Furthermore, Dg depends on Pcan but not on Laminin A for its localization in the basal-cell membrane, and the two proteins bind in vitro. Interestingly, the Dg form that interacts with Pcan in the FCE lacks the mucin-like domain, which is thought to be essential for Dg ligand binding activity. Finally, we describe two examples of how Dg promotes the differentiation of the basal membrane domain: (1) by recruiting/anchoring the cytoplasmic protein Dystrophin; and (2) by excluding the transmembrane protein Neurexin. We suggest that the interaction of Pcan and Dg at the basal side of the epithelium promotes basal membrane differentiation and is required for maintenance of cell polarity in the FCE.
TheHVE/CAND1gene is required for the early patterning of leaf venation inArabidopsis
Authors: Alonso-Peral María Magdalena , Candela Héctor , del Pozo Juan Carlos , Martínez-Laborda Antonio , Ponce María Rosa , Micol José Luis
Published: August 2006

The hemivenata-1 (hve-1) recessive allele was isolated in a search for natural variations in the leaf venation pattern of Arabidopsis thaliana, where it was seen to cause extremely simple venation in vegetative leaves and cotyledons, increased shoot branching, and reduced root waving and fertility, traits that are reminiscent of some mutants deficient in auxin signaling. Reduced sensitivity to exogenous auxin was found in the hve-1 mutant, which otherwise displayed a wild-type response to auxin transport inhibitors. The HVE gene was positionally cloned and found to encode a CAND1 protein. The hve-1 mutation caused mis-splicing of the transcripts of the HVE/CAND1 gene and a vein phenotype indistinguishable from that of hve-2 and hve-3,two putatively null T-DNA alleles. Inflorescence size and fertility were more affected by hve-2 and hve-3, suggesting that hve-1is hypomorphic. The simple venation pattern of hve plants seems to arise from an early patterning defect. We found that HVE/CAND1 binds to CULLIN1, and that the venation patterns of axr1 and hvemutants are similar, which suggest that ubiquitin-mediated auxin signaling is required for venation patterning in laminar organs, the only exception being cauline leaves. Our analyses of double mutant and transgenic plants indicated that auxin transport and perception act independently to pattern leaf veins,and that the HVE/CAND1 gene acts upstream of ATHB-8 at least in higher order veins, in a pathway that involves AXR1, but not LOP1, PIN1, CVP1 or CVP2.
General and cell-type specific mechanisms target TRPP2/PKD-2 to cilia
Authors: Bae Young-Kyung , Qin Hongmin , Knobel Karla M. , Hu Jinghua , Rosenbaum Joel L. , Barr Maureen M.
Published: August 2006

Ciliary localization of the transient receptor potential polycystin 2 channel (TRPP2/PKD-2) is evolutionarily conserved, but how TRPP2 is targeted to cilia is not known. In this study, we characterize the motility and localization of PKD-2, a TRPP2 homolog, in C. elegans sensory neurons. We demonstrate that GFP-tagged PKD-2 moves bidirectionally in the dendritic compartment. Furthermore, we show a requirement for different molecules in regulating the ciliary localization of PKD-2. PKD-2 is directed to moving dendritic particles by the UNC-101/adaptor protein 1 (AP-1) complex. When expressed in non-native neurons, PKD-2 remains in cell bodies and is not observed in dendrites or cilia, indicating that cell-type specific factors are required for directing PKD-2 to the dendrite. PKD-2 stabilization in cilia and cell bodies requires LOV-1, a functional partner and a TRPP1 homolog. In lov-1 mutants, PKD-2 is greatly reduced in cilia and forms abnormal aggregates in neuronal cell bodies. Intraflagellar transport (IFT) is not essential for PKD-2 dendritic motility or access to the cilium, but may regulate PKD-2 ciliary abundance. We propose that both general and cell-type-specific factors govern TRPP2/PKD-2 subcellular distribution by forming at least two steps involving somatodendritic and ciliary sorting decisions.
Functional analysis of Sox8 during neural crest development inXenopus
Authors: O'Donnell Michael , Hong Chang-Soo , Huang Xiao , Delnicki Raymond J. , Saint-Jeannet Jean-Pierre
Published: August 2006

Among the families of transcription factors expressed at the neural plate border, Sox proteins have been shown to regulate multiple aspects of neural crest development. Sox8, Sox9 and Sox10, exhibit overlapping expression domains in neural crest progenitors, and studies in mouse suggest that Sox8 functions redundantly with Sox9 and Sox10 during neural crest development. Here, we show that in Xenopus, Sox8 accumulates at the lateral edges of the neural plate at the mid-gastrula stage; in contrast to its mouse and chick orthologs, Sox8 expression precedes that of Sox9 and Sox10 in neural crest progenitors. Later in development, Sox8 expression persists in migrating cranial crest cells as they populate the pharyngeal arches and in trunk neural crest cells, in a pattern that recapitulates both Sox9 and Sox10 expression domains. Although morpholino-mediated knockdown of Sox8 protein did not prevent the formation of neural crest progenitors, the timing of their induction was severely affected. This delay in neural crest specification had dramatic consequences on the development of multiple lineages of the neural crest. We demonstrate that these defects are due to the inability of neural crest cells to migrate into the periphery, rather than to a deficiency in neural crest progenitors specification and survival. These results indicate that the control of Sox8 expression at the neural plate border is a key process in initiating neural crest formation in Xenopus, and highlight species-specific differences in the relative importance of SoxE proteins during neural crest development.
Suppression of thecup-5mucolipidosis type IV-related lysosomal dysfunction by the inactivation of an ABC transporter inC. elegans
Authors: Schaheen Lara , Patton Greg , Fares Hanna
Published: August 2006

Mutations in MCOLN1, which encodes the protein mucolipin 1, result in the lysosomal storage disease mucolipidosis Type IV. Studies on human mucolipin 1 and on CUP-5, the Caenorhabditis elegans ortholog of mucolipin 1, have shown that these proteins are required for lysosome biogenesis/function. Loss of CUP-5 results in a defect in lysosomal degradation, leading to embryonic lethality. We have identified a mutation in the ABC transporter MRP-4 that rescues the degradation defect and the corresponding lethality, owing to the absence of CUP-5. MRP-4 localizes to endocytic compartments and its levels are elevated in the absence of CUP-5. These results indicate that the lysosomal degradation defect is exacerbated in some cells because of the accumulation of MRP-4 in lysosomes rather than the loss of CUP-5 per se. We also show that under some conditions, loss of MRP-4 rescues the embryonic lethality caused by the loss of the cathepsin L protease, indicating that the accumulation of ABC transporters may be a more general mechanism whereby an initial lysosomal dysfunction is more severely compromised.