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The English School is one of the main traditions of thought in International Relations and the only one home-grown in Britain. While initially unconcerned with questions of integration, and the regional level more generally, its concepts and insights have recently been applied to the European integration process. However, an English School analysis of the consequences of Brexit has yet to be conducted. This article rectifies this omission and offers a broad system-level analysis of major-state withdrawal from deep multilateral arrangements. Following a brief introduction to the main phases of English School development, the article analyses the consequences of Brexit in terms of three central areas: the pluralist-solidarist debate; primary institutions; and great power status. It finds that while the adjustment costs of Brexit will be considerable, the longer-term systemic consequences are unlikely to be far-reaching. The main consequence is the additional pressure Brexit puts on Britain's precarious great power status. [ABSTRACT FROM AUTHOR]

A British withdrawal from the European Union (EU) would change Britain, the EU, the politics and security of Europe and the place of all three in the international system. To explore these possible changes, this article draws on a series of commissioned analyses that look at the views of Brexit in other EU member states and select third countries outside the EU. Specifically, it examines and maps out the prevailing ideas of what the aforementioned changes could entail. It argues that ideas connected to European unity and integration will define how a Brexit is managed. [ABSTRACT FROM PUBLISHER]

A British exit from the EU would add to growing strains on the United States' relations with Britain and the rest of Europe, but by itself would not lead to a breakdown in transatlantic relations due to the scale of shared ideas and interests, institutional links, international pressures and commitments by individual leaders. It would, however, add to pressures on the US that could change the direction of the transatlantic relationship. From the perspective of Washington, Britain risks becoming an awkward inbetweener, beholden more than ever before to a wider transatlantic relationship where the US and EU are navigating the challenges of an emerging multipolar world. The article outlines developments in the UK, EU, Europe and the US in order to explain what Brexit could mean for the United States' approaches to transatlantic relations. By doing so the article moves beyond a narrow view of Brexit and transatlantic relations that focuses on the future of UK-US relations. In the conclusion we map out several ways in which US views of the transatlantic relationship could be changed. [ABSTRACT FROM AUTHOR]

Britain's often uneasy relationship with the European Union has become increasingly strained, leading to speculation that Britain is—sooner or later—headed towards an in-out referendum that will result in its withdrawal. Such a development would present both Britain and the EU with unprecedented challenges. Britain's debate about its future in the EU—its “European question”—creates a “British question” for the EU, the answers to which could change the EU's unity, leadership, prosperity and security with implications for wider European politics and academic analysis of European integration. This article sets out the links between these two questions. It does so by considering what the future of UK–EU relations could mean for the regional politics of Europe in an emerging multipolar order. [ABSTRACT FROM AUTHOR]

The idea of holding an in/out referendum on Britain's membership of the European Union has increasingly become a norm of British politics, an act seen as a necessary step for the country to answer what David Cameron described as the 'European question in British politics'. A referendum, it is hoped, will cleanse British politics of a poisonous debate about Europe and democratically sanction a new stable UK-EU relationship, whether the UK stays in or leaves. Such hopes expect more of a referendum than it can provide. The European question is a multifaceted one and whatever the result of a referendum it is unlikely to address underlying questions that will continue to cause problems for UK-EU relations and Britain's European debate. A referendum can be a step forward in better managing the relationship and debate, but it is only that: a single step, after which further steps will be needed. Coming to terms with the European question and bringing stability to Britain's relations with the EU-whether in or outside the EU-will require comprehensive, longer-term changes which a referendum can help trigger but in no way guarantee. [ABSTRACT FROM AUTHOR]

Abstract: HMMer is a commonly used package for biological sequence database searching with profile hidden Markov model (HMMs). It allows researchers to compare HMMs to sequence databases or sequences to HMM databases. However, such searches often take many hours on traditional computer architectures. These runtime requirements are likely to become even more severe due to the rapid growth in size of both sequence and model databases. We present a new reconfigurable architecture to accelerate the two HMMer database search procedures hmmsearch and hmmpfam. It is described how this leads to significant runtime savings on off-the-shelf field-programmable gate arrays (FPGAs). [Copyright &y& Elsevier]

Rho guanosine triphosphatases (GTPases) regulate multiple aspects of dendritic cell (DC) function, but what regulates the expression of Rho GTPases in DCs is unknown. Here, we show that the extracellular matrix protein mindin regulates the expression of Rho GTPases in DCs. Mindin−/− mice displayed defective CD4+ T-cell priming and impaired humoral immune responses to T-dependent antigens. Mindin−/− DCs had reduced expression of Rac1/2 and impaired priming capacity owing to inefficient engagement with T lymphocytes. Ectopic Rac1 expression restored the priming capability of Mindin−/− DCs. Furthermore, we show that DC adhesion to mindin matrix was blocked by antibodies to α4, α5 and β1 integrins. DCs lacking β1 integrin had reduced adhesion to mindin matrix, decreased expression of Rac1/2 and impaired priming capacity. These results suggest that mindin–integrin interactions play a key role in regulating Rho GTPase expression in DCs and DC priming of T lymphocytes. [ABSTRACT FROM AUTHOR]

Investigates the separation of propulsive and adhesive traction stresses in locomoting keratocytes. Wrinkling traction force assay flowchamber; Traction patterns for gliding keratocytes; Dependence of wrinkling on actomyosin interactions; General effects of contractility inhibiting agents on keratocytes locomoting on glass.

The author reflects on the study by Vossen and colleagues which investigated the developments in stage I seminoma management. He congratulates the author for their comprehensive assessment of variation in the management throughout Eastern, Western, and Central Europe. He says that the authors were not able to cover the issue on the 78% reduction by one-day carboplatin treatment in contralateral germ cell testis tumours.

The article presents a letter to the editor in response to the article "Adjuvant carboplatin in stage I seminoma," by Padraig Warde and Mary Gospodarowicz, in the July 23, 2005 edition of "The Lancet."

Time-lapse microscopy has advanced our understanding of yolk sac and early embryonic vascularization. However, it has been difficult to assess endothelial interactions during epithelial morphogenesis of internal organs. To address this issue we have developed the first time-lapse system to study vascularization of a mammalian organ in four dimensions. We show that vascularization of XX and XY gonads is a highly dynamic, sexually dimorphic process. The XX gonad recruits vasculature by a typical angiogenic process. In contrast, the XY gonad recruits and patterns vasculature by a novel remodeling mechanism beginning with breakdown of an existing mesonephric vessel. Subsequently, in XY organs individual endothelial cells migrate and reaggregate in the coelomic domain to form the major testicular artery. Migrating endothelial cells respect domain boundaries well before they are morphologically evident, subdividing the gonad into 10 avascular regions where testis cords form. This model of vascular development in an internal organ has a direct impact on the current dogma of vascular integration during organ development and presents important parallels with mechanisms of tumor vascularization. [ABSTRACT FROM AUTHOR]

Abstract: Lung development requires reciprocal epithelial/mesenchymal interactions, mediated by signaling factors such as Bmps made in both cell populations. To address the role of Bmp signaling in the epithelium, we have exploited the fact that Bmp receptor type Ia (Alk3) is expressed in the epithelium during branching morphogenesis. Deletion of Bmpr1a in the epithelium with an Sftpc-cre transgene leads to dramatic defects in lung development. There is reduced epithelial proliferation, extensive apoptosis, changes in cell morphology and extrusion of cells into the lumen. By E18.5, there are fewer Type II cells than normal, and the lung contains large fluid-filled spaces. If cell death is prevented by making embryos homozygous null for the proapoptotic gene, Bax, the epithelial cells that are rescued can apparently differentiate, but normal morphogenesis is not restored. To determine whether Bmps made by the epithelium can function in an autocrine manner, mesenchyme-free endoderm was cultured in Matrigel™ with Fgfs. Under these conditions, the mutant epithelium fails to undergo secondary budding. Abnormal development was also seen when Bmp4 was specifically deleted in the epithelium using the Sftpc-cre transgene. Our results support a model in which Bmp signaling primarily regulates the proliferation, survival and morphogenetic behavior of distal lung epithelial cells. [Copyright &y& Elsevier]

Because the success of labor-intensive hand crosses by breeders is dependent upon pollen viability, quick, simple, and inexpensive methods for viability assessment are of interest. Four such cotton pollen viability assays were compared to determine differences in viability estimates, and relative accuracy by correlation to seed set. The methods compared were Brewbaker & Kwack (B & K) medium, B & K medium plus aniline blue, a fluorochromatic reaction method (FCR), and Alexander's stain. Additionally, digital images of germinated pollen grains were analyzed by means of morphometry software to quantify pollen tube area per pollen wain, as a proposed additional method of assessing viability. Pollen from conventional, nontreated glyphosate-resistant (GR) and glyphosate-treated GR cotton (Gossypium hirsutum L.) plants was tested by each method. Glyphosate treatments to GR cotton reduced pollen viability and corresponding seed set in all methods tested. Pollen germination measured by the B & K method was most closely related to seed set per boll, while Alexander's stain gave the highest estimates of viability. The FCR method indicated that many pollen grains from glyphosate-treated GR cotton were irregularly shaped and only partially flourescein diacetate (FD) stained. All methods tested showed similar high correlation (0.7-0.8) of pollen viability to seed set. Morphometric analysis of digital images of germinated pollen found the greatest pollen tube area to pollen grain ratio with B & K medium + 30 mM sucrose. Because the B & K method most closely predicted the linear magnitude of seed set reduction to reduced pollen viability, allowed the use of morphometry software analysis, and was one of the simplest and least equipment-demanding methods, it may provide broad utility for those assessing cotton pollen viability. [ABSTRACT FROM AUTHOR]

The article focuses on the risk factors of prostate cancer (PC) among men in the United Kingdom (UK). The risk factors include increasing age, race, family history of the PC patient, sexual factors and sexually transmitted diseases (STDs). A chart is also presented depicting the pathophysiological variables, sexual habits and the history of STD in men diagnosed with prostate cancer. A study to establish the role of sexual factors in the cause for PC would help educate people and prevent STDs.

Background: Few randomised studies have compared antiandrogen intermittent hormonal therapy (IHT) with continuous maximal androgen blockade (MAB) therapy for advanced prostate cancer (PCa). Objective: To determine whether overall survival (OS) on IHT (cyproterone acetate; CPA) is noninferior to OS on continuous MAB. Design, setting, and participants: This phase 3 randomised trial compared IHT and continuous MAB in patients with locally advanced or metastatic PCa. Intervention: During induction, patients received CPA 200 mg/d for 2 wk and then monthly depot injections of a luteinising hormone-releasing hormone (LHRH; triptoreline 11.25 mg) analogue plus CPA 200 mg/d. Patients whose prostate-specific antigen (PSA) was <4 ng/ml after 3 mo of induction treatment were randomised to the IHT arm (stopped treatment and restarted on CPA 300 mg/d monotherapy if PSA rose to ≥20 ng/ml or they were symptomatic) or the continuous arm (CPA 200 mg/d plus monthly LHRH analogue). Outcome measurements and statistical analysis: Primary outcome measurement was OS. Secondary outcomes included cause-specific survival, time to subjective or objective progression, and quality of life. Time off therapy in the intermittent arm was recorded. Results and limitations: We recruited 1045 patients, of which 918 responded to induction therapy and were randomised (462 to IHT and 456 to continuous MAB). OS was similar between groups (p = 0.25), and noninferiority of IHT was demonstrated (hazard ratio [HR]: 0.90; 95% confidence interval [CI], 0.76-1.07). There was a trend for an interaction between PSA and treatment (p = 0.05), favouring IHT over continuous therapy in patients with PSA ≤1 ng/ml (HR: 0.79; 95% CI, 0.61-1.02). Men treated with IHT reported better sexual function. Among the 462 patients on IHT, 50% and 28% of patients were off therapy for ≥2.5 yr or >5 yr, respectively, after randomisation. The main limitation is that the length of time for the trial to mature means that other therapies are now available. A second limitation is that T3 patients may now profit from watchful waiting instead of androgen-deprivation therapy. Conclusions: Noninferiority of IHT in terms of survival and its association with better sexual activity than continuous therapy suggest that IHT should be considered for use in routine clinical practice. Take Home Message: Intermittent hormone monotherapy with cyproterone acetate 300 mg/d was noninferior to maximal androgen blockade in patients with advanced prostate cancer with respect to overall survival. Intermittent therapy was also associated with greater sexual activity. [ABSTRACT FROM AUTHOR]

Abstract: Background: Testicular cancer is the most common cancer in men under 35 years of age, and has the highest survival for adult male malignancies. Despite the fact that survival is very high, there is evidence that survival differs between socio-economic groups. Methods: We analysed survival patterns for 1606 testicular cancer patients diagnosed during 1984–2001 and recruited to one of two clinical studies. The first was a surveillance study to determine relapse-free survival after orchidectomy in 865 patients with stage I nonseminomatous germ-cell testicular cancer diagnosed during 1984–1991 (TE04). The second study was a trial in which 1174 men with stage I seminomatous germ-cell tumours were randomised to receive radiotherapy or one injection of carboplatin between 1996 and 2001 (TE19). The number of men available for analysis from these two studies was 578 and 1028, respectively. We followed these patients up for their vital status, and assigned them an ecological measure of deprivation. Crude and relative survival were estimated at 5 and 10 years by socio-economic deprivation. Results: No significant socio-economic gradient was seen: 1.3% (95% CI −0.3% to 3.1%) at 5 years and 2.1% (95% CI −0.5% to 4.7%) at 10 years. Conclusion: We conclude that, given equal treatment at a given stage of disease, survival from testicular cancer does not depend on socio-economic status. This suggests that the socio-economic gradient in testicular cancer survival in the general population is more likely to be attributable to health care system factors than to personal or socio-economic factors in the men themselves. [Copyright &y& Elsevier]

The immunity-related GTPases (IRGs) are a family of proteins induced by interferon-? that play a crucial role in innate resistance to intracellular pathogens. The M subfamily of IRG proteins (IRGM) plays a profound role in this context, in part because of the ability of its members to regulate the localization and expression of other IRG proteins. We present here evidence that IRGM proteins affect the localization of the guanylate-binding proteins (GBPs), a second family of interferon-induced GTP-binding proteins that also function in innate immunity. Absence of Irgm1 or Irgm3 led to accumulation of Gbp2 in intracellular compartments that were positive for both the macroautophagy (hereafter referred to as autophagy) marker LC3 and the autophagic adapter molecule p62/Sqstm1. Gbp2 was similarly relocalized in cells in which autophagy was impaired because of the absence of Atg5. Both in Atg5- and IRGM-deficient cells, the IRG protein Irga6 relocalized to the same compartments as Gbp2, raising the possibility of a common regulatory mechanism. However, other data indicated that Irga6, but not Gbp2, was ubiquitinated in IRGM-deficient cells. Similarly, coimmunoprecipitation studies indicated that although Irgm3 did interact directly with Irgb6, it did not interact with Gbp2. Collectively, these data suggest that IRGM proteins indirectly modulate the localization of GBPs through a distinct mechanism from that through which they regulate IRG protein localization. Further, these results suggest that a core function of IRGM proteins is to regulate autophagic flux, which influences the localization of GBPs and possibly other factors that instruct cell-autonomous immune resistance. [ABSTRACT FROM AUTHOR]

Background: Human respiratory epithelia function in airway mucociliary clearance and barrier function and have recently been implicated in sensory functions. oBjective: We investigated a link between chronic obstructive pulmonary disease (COPD) patho­genesis and molecular mechanisms underlying Ca2+ influx into human airway epithelia elicited by diesel exhaust particles (DEP). Methods and results: Using primary cultures of human respiratory epithelial (HRE) cells, we determined that these cells possess proteolytic signaling machinery, whereby proteinase-activated receptor-2 (PAR-2) activates Ca2+-permeable TRPV4, which leads to activation of human respira­tory disease-enhancing matrix metalloproteinase-1 (MMP-1), a signaling cascade initiated by diesel exhaust particles (DEP), a globally relevant air pollutant. Moreover, we observed ciliary expression of PAR-2, TRPV4, and phospholipase-C?3 in human airway epithelia and their DEP-enhanced protein-protein complex formation. We also found that the chronic obstructive pulmonary disease (COPD)-predisposing TRPV4P19S variant enhances Ca2+ influx and MMP 1 activation, providing mechanistic linkage between man-made air pollution and human airway disease. conclusion: DEP evoked protracted Ca2+ influx via TRPV4, enhanced by the COPD-predisposing human genetic polymorphism TRPV4P19S. This mechanism reprograms maladaptive inflammatory and extracellular-matrix-remodeling responses in human airways. The novel concept of air pollu­tion-responsive ciliary signal transduction from PAR-2 to TRPV4 in human respiratory epithelia will accelerate rationally targeted therapies, possibly via the inhalatory route. [ABSTRACT FROM AUTHOR]

The article discusses a study on the prognostic significance of a combined dexamethasone and diethylstilbestrol (DS) therapy by measuring the prostate-specific antigen (PSA) level before and after a month of DS therapy. An assessment of the prognostic patients factors was done 30 days after the start of DS therapy. The study indicates that the prognostic index developed showed the possibility of identifying patients with castrate-resistant prostate cancer (CRPC) who had a good prognosis within a month of DS therapy.

Germ cell tumours (GCT) can become resistant to cisplatin, which is associated with a relatively poor prognosis. Oxaliplatin and satraplatin have been developed to overcome cisplatin resistance in other cancers, but their effect in cisplatin resistant (cisR) GCTs is unclear. In this work we address this issue by comparing their efficacy in three paired sensitive and cisR GCT cell lines. Three established cisplatin sensitive (cisS) and resistant cell line pairs were used (GCT27, GCT27r: SUSA, SUSAr: 833k, 833kr). Viability was assessed using a luciferase based ATP assay and EC50 and EC80 concentrations were calculated. Western blot analysis and flow cytometry was used for further assessment. Sensitivity to the three platinum compounds was broadly similar in the three cisS lines GCT cell lines (EC50 = 0.27–0.51 μM for cisplatin, 0.52–0.79 μM for oxaliplatin, 0.31–1.26 μM for satraplatin). EC50 values for cisplatin in the three cisR sub lines were 1.8- to 3.8-fold higher than in the sensitive parental lines. Cross resistance to satraplatin and oxaliplatin occurred in all three cisR cell lines (resistance factor 1.9–4.4), with the exception of oxaliplatin in the 833Kr (resistance factor 0.9). Differences in the effect of specific drugs on cell cycle distribution, p53, p21 and MDM2 were observed. These data suggest that satraplatin and oxaliplatin could theoretically be used in chemo-naive GCTs and support the further clinical evaluation of these agents in this setting. The mechanism of cross resistance to these drugs appears multifactorial. [ABSTRACT FROM AUTHOR]

Abstract: Objectives: Men with clinically detected localized prostate cancer treated without curative intent are at risk of complications from local tumor growth. We investigated rates of local progression and need for local therapy among such men. Methods: Men diagnosed with prostate cancer during 1990–1996 were identified from cancer registries throughout the United Kingdom. Inclusion criteria were age ≤76 yr at diagnosis, PSA level ≤100ng/ml, and, within 6 mo after diagnosis, no radiation therapy, radical prostatectomy, evidence of metastatic disease, or death. Local progression was defined as increase in clinical stage from T1/2 to T3/T4 disease, T3 to T4 disease, and/or need for transurethral resection of the prostate (TURP) to relieve symptoms >6 mo after cancer diagnosis. Results: The study included 2333 men with median follow-up of 85 mo (range: 6–174). Diagnosis was by TURP in 1255 men (54%), needle biopsy in 1039 (45%), and unspecified in 39 (2%). Only 29% were treated with hormonal therapy within 6 mo of diagnosis. Local progression occurred in 335 men, including 212 undergoing TURP. Factors most predictive of local progression on multivariable analysis were PSA at diagnosis and Gleason score of the diagnostic tissue (detrimental), and early hormonal therapy (protective). We present a nomogram that predicts the likelihood of local progression within 120 mo after diagnosis. Conclusions: Men with clinically detected localized prostate cancer managed without curative intent have an approximately 15% risk for local progression within 10 yr of diagnosis. Among those with progression, the need for treatment is common, even among men diagnosed by TURP. When counseling men who are candidates for management without curative intent, the likelihood of symptoms from local progression must be considered. [Copyright &y& Elsevier]

Background: The prognosis of men with clinically localized prostate cancer is highly variable, and it is difficult to counsel a man who may be considering avoiding, or delaying, aggressive therapy. After collecting data on a large cohort of men who received no initial active prostate cancer therapy, the aim was to develop, and to internally validate, a nomogram for prediction of disease-specific survival.Methods: Working with 6 cancer registries within England and numerous hospitals in the region, a population-based cohort of men diagnosed with prostate cancer between 1990 and 1996 was constructed. All men had baseline serum prostate-specific antigen (PSA) measurements, centralized pathologic grading, and centralized review of clinical stage assignment. Based on the clinical and pathologic data from 1911 men, a statistical model was developed and validated that served as the basis for the nomogram. The discrimination and calibration of the nomogram were assessed with use of one-third of the men, who were omitted from modeling and used as a test sample.Results: The median age of the included men was 70.4 years. The 25th and 75th percentiles of PSA were 7.3 and 32.6 ng/mL respectively, and the median was 15.4 ng/mL. Forty-two percent of the men had high-grade disease. The nomogram predicted well, with a concordance index of 0.73, and had good calibration.Conclusions: An accurate tool was developed for predicting the probability that a man with clinically localized prostate cancer will survive his disease for 120 months if the cancer is not treated with curative intent immediately. The tool should be helpful for patient counseling and clinical trial design. [ABSTRACT FROM AUTHOR]

Background: Oxaliplatin is a 3rd generation platinum analogue, which is active in a broad spectrum of tumours. Clinical trials using this drug in bladder cancer are underway, but not yet reported. There are currently no in vitro data regarding oxaliplatin in bladder cancer. Therefore, this study compares the efficacy of oxaliplatin with cisplatin and carboplatin, which are both used widely in this tumour type, in bladder cancer cell lines. Method: The efficacy of oxaliplatin, carboplatin and cisplatin were compared in 4 bladder cancer cell lines (5637, J82, HT1197 and 253J). Cell parameters including cell number, viability and apoptosis were assessed after 3 days of drug exposure. The effects of the drugs on the cell cycle were also observed. Results: Overall cisplatin was the most potent at inducing cell death (IC50 11.5–70.6 μM). Oxaliplatin was the 2nd most potent drug (IC50 15.2–126.3 μM) and carboplatin the least effective (IC50 75.4–137.8 μM). Carboplatin was significantly less potent at inducing cell death than the other two drugs in all 4 cell lines. Carboplatin was also inferior at inducing apoptosis in 3 of the 4 cell lines. All three drugs had a similar effect on the cell cycle, causing an initial G2 block. Conclusions: These data suggest that oxaliplatin is a potent agent in bladder cancer cell lines and is superior to carboplatin in this in vitro setting. It justifies the clinical studies using oxaliplatin that are underway. Copyright © 2007 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Abstract: Objectives: Positron emission tomography (PET) provides unique insights into molecular pathways of diseases. PET using [F-18]-fluorodeoxyglucose (FDG) has gained increasing acceptance for the diagnosis, staging, and treatment monitoring of various tumour types. The aim of this review is to provide an update on the current status of molecular PET and PET/CT imaging in urological malignancies. Methods: The current literature on PET and PET/CT imaging was reviewed and summarized for prostate cancer, bladder cancer, renal cell carcinoma, and germ cell tumours. Results: Depending on the radiotracer used, PET offers diagnostic information based on glucose, choline or amino acid metabolism and has also been applied to imaging tumour cell proliferation and tissue hypoxia in urological malignancies. The diagnostic performance of FDG-PET is hampered by the renal excretion of FDG and by the low metabolic activity often seen in tumours such as prostate cancer. However, new PET tracers including radiolabelled choline and acetate may offer an alternative approach. There is consistent evidence that FDG-PET provides important diagnostic information in detecting metastatic and recurrent germ cell tumours and it might offer additional information in the staging and restaging of bladder and renal cancer. Conclusions: Although PET imaging has been shown to be a clinically useful tool, its application in urological malignancies still needs to be fully determined by larger prospective trials. The introduction of novel PET radiopharmaceuticals along with the new technology of PET/CT will likely change the future role of molecular imaging in urological malignancies. [Copyright &y& Elsevier]

OBJECTIVE To review pooled phase II data to identify features of different regimens of intermittent hormone therapy (IHT), developed to reduce the morbidity of treating metastatic prostate cancer, and which carries a theoretical advantage of delaying the onset of androgen-independent prostate cancer, (AIPC) that are associated with success, highlighting features which require exploration with prospective trials to establish the best strategies for using this treatment. METHODS Individual data were collated on 1446 patients with adequate information, from 10 phase II studies with >50 cases, identified through Pubmed. RESULTS Univariate and multivariate Cox proportional hazard models were developed to predict treatment success with a high degree of statistical success. The prostate-specific antigen (PSA) nadir, the PSA threshold to restart treatment, and medication type and duration, were important predictors of outcome. CONCLUSIONS The duration of biochemical remission after a period of HT is a durable early indicator of how rapidly AIPC and death will occur, and will make a useful endpoint in future trials to investigate the best ways to use IHT based on the important treatment cycling variables described above. Patients spent a mean of 39% of the time off treatment. The initial PSA level and PSA nadir allow the identification of patients with prostate cancer in whom it might be possible to avoid radical therapy. [ABSTRACT FROM AUTHOR]

The molecular mechanism and significance of endocytic processes involved in directional axon elongation are not well understood. The Unc-51 family of serine/threonine kinases was shown to be important for axon growth and was also linked to endocytosis, providing an entry point to study this problem. We found that mouse Unc-51-like kinase 1/2 (Ulk1/2) proteins are localized to vesicular structures in growth cones of mouse spinal sensory neurons. RNAi-mediated knockdown of Ulk1 and/or Ulk2 resulted in impaired endocytosis of nerve growth factor (NGF), excessive axon arborization, and severely stunted axon elongation. The evidence also indicates that Ulk1/2 mediates a non-clathrin-coated endocytosis in sensory growth cones. Interestingly, NGF can induce the interaction of Ulk1 with TrkA receptor complexes through promoting K63-polyubiquitination of Ulk1 and binding of Ulk1 to the scaffolding protein p62. These results and additional studies suggest that Ulk1/2 proteins regulate filopodia extension and neurite branching during sensory axon outgrowth, probably through regulating TrkA receptor trafficking and signaling. [ABSTRACT FROM AUTHOR]

OBJECTIVE To determine whether there are ethnic differences in the incidence and presenting features of all patients with prostate cancer presenting in North-east London, UK. PATIENTS AND METHODS All newly diagnosed men with prostate cancer between 1999 and 2000 who were resident in the East London and City Health Authority were identified from various sources. Key clinical features were extracted from hospital records. The age-adjusted incidence rates for European, South Asian and African-Caribbean patients were calculated using census denominator data. RESULTS For men aged >50 years the annual age-adjusted incidence rates (95% confidence interval) were 213 (186–240), 647 (504–789) and 199 (85–310) for the European, African-Caribbean and South Asian patients, respectively. African-Caribbean men had a three times greater risk (risk ratio 3.07, 2.40–3.93, P < 0.001) than European men. South Asian men had a lower risk of prostate cancer but this could have been compatible with chance. There was no evidence of marked ethnic differences for prostate-specific antigen levels, clinical staging and Gleason scores. CONCLUSION The greater risk of prostate cancer for African-Caribbean men in South-east England is consistent with data from the USA and the Caribbean. Future work needs to determine whether this risk differs according to country of origin, and which genetic and/or environmental risk factors might be important in explaining these observations. [ABSTRACT FROM AUTHOR]

Authors from London looked at patients diagnosed with germ cell tumours of the testis who presented between 1983 and 2002. They found that there was an overall increase in the percentage of patients presenting with stage I seminoma, with a significant reduction in the size of the primary tumour. The authors do not feel that they can clarify the reason for these changes. There is a 20-year follow-up of patients who had tumours of the ureter and renal pelvis treated with resection and renal autotransplantation. In this fascinating series from Gothenberg, it was found that in patients with a normal contralateral kidney, resection and autotransplantation was not indicated. It was possibly beneficial in patients with solitary kidneys, but only after other treatments have been considered. To prospectively investigate the presentation of germ cell tumours (GCTs) of the testis in terms of stage or histology, as the incidence of this disease in increasing. Patients diagnosed with GCT of the testis between 1983 and 2002 were categorised into three periods depending on the date of diagnosis of the GCT, and the presentational characteristics assessed. There was a significant increase in the proportion of patients presenting with stage I disease (59% to 78%) and seminoma (43% to 58%) over this period. There was also a significant reduction in the size of the primary tumour (5 to 4 cm). A greater proportion of patients with GCT are presenting with stage I seminoma, the reasons for which are unclear, although earlier diagnosis through improved awareness of GCT may be important. [ABSTRACT FROM AUTHOR]

Abstract: Here we report the complex pattern of genomic imbalances and rearrangements in a panel of 19 renal cell carcinoma cell lines detected with molecular cytogenetic analysis. Consistent heterogeneity in chromosome number was found, and most cell lines showed a near-triploid chromosome complement. Several cell lines showed deletions of the TP53 (alias p53), CDKN2A (alias p16), and VHL genes. Multiplex fluorescence in situ hybridization (M-FISH) analysis revealed chromosome 3 translocated to several other partners chromosomes, as well as breakage events commonly affecting chromosomes 1, 5, 8, 10, and 17. The most common abnormality detected with comparative genomic hybridization (CGH) was deletions of chromosome 3p, with loss of the RASSF1, FHIT, and p44S10 loci frequently involved. CGH gain of 5q showed overrepresentation of the EGR1 and CSF1R genes. Recurrent alterations to chromosome 7 included rearrangement of 7q11 and gains of the EGFR, TIF1, and RFC2 genes. Several lines exhibited rearrangement of 12q11∼q14 and overrepresentation of CDK4 and SAS loci. M-FISH revealed several other recurrent translocations, and CGH findings included loss of 9p, 14q, and 18q and gain of 8q, 12, and 20. Further genomic microarray changes included loss of MTAP, IGH@, HTR1B, and SMAD4 (previously MADH4) and gains of MYC and TOP1. An excellent correlation was observed between the genomic array and FISH data, demonstrating that this technique is effective and accurate. The aberrations detected here may reflect important pathways in renal cancer pathogenesis. [Copyright &y& Elsevier]

The recombinant growth factors (GFs) erythropoietin (Epo) and granulocyte-macrophage colony stimulating factor (GM-CSF) have important roles in the management of cancer patients. However, the effects of these GFs at a cellular level are not well understood. We examined the effect of GFs alone, and in combination with cytotoxic chemotherapy, in a panel of seven cell lines. Flow cytometric analysis showed varying levels of receptor expression, which correlated with phosphorylated MAPK expression. Additionally, there were also concomitant increases in BCL-2 protein levels in those cells with high levels of MAPK activation. Although culturing cells with Epo or GM-CSF did not alter cell viability by themselves, GF pretreatment in cell lines expressing higher receptor levels resulted in a reduced magnitude of cell kill following exposure to cytotoxic IC50 concentrations of cisplatin. Subsequent co-culture with either the MEK inhibitor U0126 or the GM-CSF antagonist E21R negated this induced resistance to cytotoxic chemotherapy, confirming the importance of the GF receptor as well as MAPK in mediating these effects. These results suggest that the use of GFs during chemotherapy may be detrimental in those cancers expressing higher levels of the specific receptor. Conversely, our results also suggest that GFs are safe to use in chemotherapeutic regimens if the cancer cells do not overexpress the particular receptor.Oncogene (2004) 23, 981-990. doi:10.1038/sj.onc.1207294 Published online 1 December 2003 [ABSTRACT FROM AUTHOR]

Nonseminomatous germ cell cancers (NSGCC) have a varied response to chemotherapy, some melting away with resultant cure, some have tumour stem cell necrosis and residual benign disease whilst others are resistant to treatment. The latter two require surgical excision in order to identify those needing high intensity chemotherapy. Objective: The aim of this study was to investigate whether it was possible to give an earlier prediction of need for surgery after chemotherapy on the basis of a limited CT scan performed after the first course. Materials and Methods: Twenty-three patients with metastatic NSGCC undergoing induction chemotherapy were studied. The site of the maximum disease was noted before treatment and only this area was rescanned at day 21. The change in disease bulk, measured as maximum transverse diameter (MTD), was compared with appearances on a CT scan immediately after chemotherapy and post-treatment response. Results: Of those patients showing a poor response on the day 21 scan (i.e. no change, or less than 50% reduction in MTD), 70% required early surgical excision of residual disease, while none of the good responders (i.e. greater than 50% reduction in MTD), required immediate surgery (p < 0.001). Conclusion: It is concluded that a limited day 21 CT scan may represent an independent predictor of good and poor response to chemotherapy, thus enabling reduction in chemotherapy and its toxicity in good responders and early identification of those who may need surgical excision, thereby permitting easier scheduling of these often difficult surgical procedures. [ABSTRACT FROM AUTHOR]