Search

BACKGROUND: Cyclin E1 (CCNE1) is a potential predictive marker and therapeutic target in tubo-ovarian high-grade serous carcinoma (HGSC). Smaller studies have revealed unfavorable associations for CCNE1 amplification and CCNE1 overexpression with survival, but to date no large-scale, histotype-specific validation has been performed. The hypothesis was that high-level amplification of CCNE1 and CCNE1 overexpression, as well as a combination of the two, are linked to shorter overall survival in HGSC. METHODS: Within the Ovarian Tumor Tissue Analysis consortium, amplification status and protein level in 3029 HGSC cases and mRNA expression in 2419 samples were investigated. RESULTS: High-level amplification (>8 copies by chromogenic in situ hybridization) was found in 8.6% of HGSC and overexpression (>60% with at least 5% demonstrating strong intensity by immunohistochemistry) was found in 22.4%. CCNE1 high-level amplification and overexpression both were linked to shorter overall survival in multivariate survival analysis adjusted for age and stage, with hazard stratification by study (hazard ratio [HR], 1.26; 95% CI, 1.08-1.47, p = .034, and HR, 1.18; 95% CI, 1.05-1.32, p = .015, respectively). This was also true for cases with combined high-level amplification/overexpression (HR, 1.26; 95% CI, 1.09-1.47, p = .033). CCNE1 mRNA expression was not associated with overall survival (HR, 1.00 per 1-SD increase; 95% CI, 0.94-1.06; p = .58). CCNE1 high-level amplification is mutually exclusive with the presence of germline BRCA1/2 pathogenic variants and shows an inverse association to RB1 loss. CONCLUSION: This study provides large-scale validation that CCNE1 high-level amplification is associated with shorter survival, supporting its utility as a prognostic biomarker in HGSC. ispartof: CANCER vol:129 issue:5 pages:697-713 ispartof: location:United States status: published

Post-traumatic stress disorder (PTSD) is a significant public health problem especially among first responders who are routinely exposed to traumatic events. First responders in rural areas are faced with additional stressors. The purpose of this quality improvement program was to implement PTSD screening for first responders at a primary care concierge clinic.Implementation of PTSD screening program among first responders was conducted from October to December 2020, using the PTSD Checklist for DSM-5 with Life Events Checklist for DSM-5 and Criterion A (PCL-5 with LEC-5 and Criterion A).First responders who visited the clinic during program implementation period.Numbers of PTSD screening, positive screening, positive PTSD symptoms, and referral.Thirty-four first responders completed the PTSD screening. 23.5% (n = 8) of first responders were screened positive. Almost 80% of first responders reported experiencing at least one PSTD symptom (n = 27). Six of the eight screened positive first responders (75%) received a referral.The standardized PTSD screening protocol utilizing PCL-5 was effective to identify first responders with PTSD. It can be integrated into the workflow of a primary care concierge clinic and help improving PTSD assessment in first responders and initiated referrals.

BACKGROUND Simulation-based training is an effective method of enhancing the knowledge, skill, and technical abilities of individuals and teams encountering obstetric and gynaecologic emergencies. Simulation may also enhance the non-technical performance of teams resulting in improved patient outcomes. Although simulation-based training is widely recognised as an effective educational approach, issues around feasibility - the lack of simulation experts and malleable outcome measures of team performance - remain critical barriers to their implementation. AIM To evaluate the psychometric properties of the Team Emergency Assessment Measure (TEAM) when used by medical professionals in simulated obstetric and gynaecological emergencies. METHODS There were 151 participants (63% female; 60% consultants; 69% no previous simulation-based training) who observed three live high-fidelity obstetric and gynaecological resuscitation simulations and completed the TEAM. RESULTS Confirmatory factor analysis evaluated the construct validity of the TEAM, yielding a second-order structure identified by 'leadership', 'teamwork', and 'team management'. Convergent validity was supported by the average item-to-scale total correlation which was 0.75, P

We introduce a strategy to optimize the photoswitching behavior of rhodamines for (d)STORM super-resolution microscopy. By replacing the benzene ring in the rhodamine core with a permanently charged 1,3-disubstituted imidazolium, the resultant dyes are markedly sensitized toward photoswitching, and exhibit outstanding (d)STORM performance with fast on-off switching, long-lasting blinking, and bright single-molecule emission. We thus attain excellent (d)STORM images under green excitation that are on par with the "ideal" red-excited dyes, including for difficult structures such as the mammalian actin cytoskeleton, and demonstrate high-quality two-color three-dimensional (d)STORM.

Pre‐trial detention plays an important, and often contentious, role in the criminal justice process. Legal theorists have gone to great lengths to distinguish between preventive detention and punishment with respect to pre‐trial detention, as it would violate the principle of retribution and the presumption of innocence if yet‐to‐be convicted defendants were subjected to punishment. Nonetheless, the experiences of detainees remains an understudied area. The purpose of this article is not to dispute whether pre‐trial detention is, or can be justified as, a form of punishment, but it is to show that pre‐trial detention, at least in the minds of detained defendants, is punitive. Drawing on interviews with a sample of previously‐detained defendants in Hong Kong, it is found that they experience censure (stigma) and hard treatment during their time in pre‐trial detention. Implications and recommendations are discussed.

Aims Micropapillary carcinomas, or carcinomas with a micropapillary component, are well recognised in the breast and other anatomical sites. However, they have seldom been described in the cervix. In this article, we present a clinicopathological analysis of eight cervical tumours that showed at least a focal (≥5%) component of micropapillary carcinoma. Methods and results The study group comprised eight cervical carcinomas (four adenocarcinomas and four adenosquamous carcinomas) with a micropapillary component. The median patient age was 41.5 years (range 27-65 years). At presentation, five patients were stage IB, two were stage IIB, and one was stage IV. The micropapillary component accounted for ≤25% of the tumour on initial biopsy or resection specimens in all but one case. Immunohistochemistry showed 'inside-out' (reverse polarity) mucin 1 staining along the cell membrane abutting the stroma. Four patients developed metastasis, all of whom showed a pure micropapillary pattern; this led to a misdiagnosis of an apparently independent peritoneal serous carcinoma in one case. All tumours showed diffuse p16 expression, and all three cases that were tested were positive for human papillomavirus (HPV) 18. Three of the six patients with at least 12 months of follow-up died of disease, and one is alive with distant metastasis. Conclusions Usual-type (HPV-related) cervical carcinomas may show micropapillary differentiation, usually as a focal finding, and the cells show reverse polarity like similar tumours arising in other sites. Micropapillary cervical carcinoma appears to be a clinically aggressive malignancy, although this needs to be confirmed in larger studies.

Summary Work in the past 10 years has greatly expanded our understanding of Alzheimer's disease (AD) genetics, with more than 20 susceptibility genetic loci discovered in large genome-wide association and sequencing studies. The NIA Genetics of Alzheimer's Disease Data Storage Site (NIAGADS) is funded by National Institute on Aging to serve as a one-stop portal for the community to access research data and findings generated from AD genetics projects. In this article, we describe the mission of NIAGADS, available resources, and data sets including the Alzheimer's Disease Sequencing Project, and how researchers may apply for access to genetic data.

Metastasis is a crucial step of malignant progression and is the primary cause of death from endometrial cancer. However, clinicians presently face the challenge that conventional surgical-pathological variables, such as tumour size, depth of myometrial invasion, histological grade, lymphovascular space invasion or radiological imaging are unable to predict with accuracy if the primary tumour has metastasized. In the current retrospective study, we have used primary tumour samples of endometrial cancer patients diagnosed with (n = 16) and without (n = 27) lymph nodemetastasis to identify potential discriminators. Using peptide matrix assisted laser desorption/ionisation mass spectrometry imaging (MALDI-MSI), we have identified m/z values which can classify 88% of all tumours correctly. The top discriminative m/z values were identified using a combination of in situ sequencing and LC-MS/MS from digested tumour samples. Two of the proteins identified, plectin and alpha-Actin-2, were used for validation studies using LC-MS/MS data independent analysis (DIA) and immunohistochemistry. In summary, MALDI-MSI has the potential to identify discriminators of metastasis using primary tumour samples. Refereed/Peer-reviewed

Fusarium species are environmental saprophytic fungi. Among the many Fusarium species, members of the Fusarium solani species complex (FSSC) are the most prevalent and virulent in causing human and animal infections. In this study, we describe the first case of fatal FSSC infection in a black spotted stingray and three concomitant infections in scalloped hammerhead sharks. In the stingray, cutaneous lesions were characterised by ulcers and haemorrhage of the ventral pectoral fin, or 'ray', especially around the head; while cutaneous lesions in the sharks were characterised by ulcers, haemorrhage, as well as white and purulent exudates at the cephalic canals of the cephalofoil and lateral line. Histological sections of the cutaneous lesions revealed slender (1-4 μm in diameter), branching, septate fungal hyphae. Internal transcribed spacer region and 28S nrDNA sequencing of the fungal isolates from the fish showed two isolates were F. keratoplasticum (FSSC 2) and the other two were FSSC 12. Environmental investigation revealed the FSSC strains isolated from water and biofilms in tanks that housed the elasmobranchs were also F. keratoplasticum and FSSC 12. Fusarium is associated with major infections in elasmobranchs and FSSC 12 is an emerging cause of infections in marine animals. DNA sequencing is so far the most reliable method for accurate identification of Fusarium species.

This article investigates the year-to-year variability of the onset of the South China Sea summer monsoon (SCSSM) and the possible influences exerted by the surface temperature anomalies over land and sea. Early and late monsoon onsets are related to the temperature anomalies in different regions. It is found that an early onset follows negative sea surface temperature (SST) anomalies in the central tropical Pacific (CP) Ocean during the preceding winter and spring, corresponding to a CP La Nina. In contrast, a late onset is preceded by the negative surface air temperature anomalies over land in the central Asian continent. Negative SST anomalies in the central-eastern equatorial Pacific Ocean and the associated warming in the western Pacific induce an anomalously enhanced Walker circulation. This anomalous Walker cell leads to an increase in convection, causing more latent heat release and a subsequent decrease of surface pressure. The anomalous Walker cell and the enhanced latent heat release weaken the Western North Pacific subtropical high and the Philippine Sea anticyclone, favouring a westerly flow from the Indian Ocean, resulting in an early SCSSM onset. On the other hand, negative land surface temperature anomalies cool the atmosphere over land, and locally modify the Hadley circulation, accompanied by the anomalous divergence in the low-level atmosphere over the western equatorial Pacific. This divergence anomaly reduces the latent heat release and strengthens the anticyclone in the Philippine Sea, thus preventing the westward extension of the westerlies from the Indian Ocean and causing a late SCSSM onset.

Aims To perform a population-based review of monomorphic endometrial stromal tumours and their histological mimics presenting over a 20-year period, including an evaluation of fluorescence in-situ hybridization (FISH) for the JAZF1 and YWHAE breakaparts. Methods and results Forty-nine tumours were examined, comprising 13 histological mimics and 36 endometrial stromal tumours [six stromal nodules (ESNs), 25 low-grade stromal sarcomas (ESSs), and five monomorphic undifferentiated sarcomas (mUESs)]. Nine ESSs showed variant histological patterns, including smooth muscle, sex cord-like/glandular, fibrous or rhabdoid differentiation. Three ESSs were initially misclassified as benign uterine lesions, and, conversely, three benign mimics were originally reported as ESSs. One mUES showed a prominent pseudopapillary pattern. Fluorescence in-situ hybridization demonstrated JAZF1 breakaparts in five of six ESNs and 16 of 25 ESSs; however, only three of nine ESS variants were positive. YWHAE breakaparts were present in four of five mUESs. Analysis of a subsequent metastasis in the YWHAE breakapart-negative mUES demonstrated a YWHAE deletion. None of the histological mimics was positive in FISH analysis. Diffuse cyclin D1 expression was restricted to mUESs in this series. Conclusions Endometrial stromal neoplasms continue to present diagnostic difficulty. Fluorescence in-situ hybridization analysis is helpful in distinguishing stromal tumours from their histological mimics and in distinguishing ESS from mUES.

Introduction Whilst the prime role of a gynaecologic oncologist is the comprehensive management of women with a gynaecologic cancer, their surgical skills are increasingly utilised for general gynaecological and obstetric surgery. Within tertiary centres, there is increasing provision of support by gynaecologic oncologists for both emergency and complex elective cases. Aim The aim of the study was to investigate and define the expanding role of the gynaecologic oncologist within obstetrics and gynaecology. Method A retrospective analysis of all nongynaecological oncology unit cases from 2006 to 2012 which required the presence of a gynaecologic oncologist in the operating theatre. Results A wide variety of cases that required the involvement of a gynaecologic oncologist were identified. These ranged from complications such as bowel injuries and haemorrhage to gynaecological surgeries in complicated patients, and obstetric patients with placenta accreta and intra-operative diagnosis of unexpected malignancy. Conclusion The role of the gynaecologic oncologist within a tertiary centre is expanding to include the provision of support to general gynaecologists and obstetricians. There is increasing utilisation of the gynaecologic oncologist whereby their attendance is often pre-arranged prior to the surgery. However, emergency cases requiring their assistance are not uncommon.

We propose the concept of intrinsic spatial distance (ISD) for the study of a spatial relationship between any two points in space. ISD is a distance measure that takes into account the separation of two points with respect to their physical and attribute closeness. We construct an algorithm to implement this concept as an ISD measurement. Based on the ISD concept, two points in space are related through a transitional path linking one to the other. As an ISD measurement decreases, the spatial relationship between two points becomes increasingly stronger. We argue theoretically and demonstrate empirically that the ISD concept is not predisposed in favor of the first law of geography, but directly considers variance of nearness in physical distance and attribute distance to derive the extent to which two points are spatially associated. Specifically, in single attribute cases, the information uncovered by an ISD measurement is more elaborate than that revealed by Moran's I, local Moran's I, and a semivariogram, giving a meticulous account of relatedness in both local and global contexts. The ISD concept is also sufficiently general to be used to study multiple attributes of relationships. Proponemos el concepto de distancia espacial intrinseca (intrinsic spatial distance -ISD) para el estudio de la relacion espacial entre dos puntos en el espacio. La ISD es una medicion de distancia que tiene en cuenta la separacion de dos puntos con respecto a su cercania fisica y de atributo. Construimos un algoritmo para aplicar este concepto y crear una medicion ISD. De acuerdo con en el concepto ISD, dos puntos en el espacio estan relacionadas a traves de un camino de transicion que los vincula uno al otro. A medida que la medicion ISD disminuye, la relacion espacial entre dos puntos se refuerza. Argumentamos teoricamente y demostramos empiricamente que el concepto ISD no esta predispuesto a favor de la primera ley de la geografia (de Tobler), pero considera directamente la varianza de la cercania de la distancia fisica y la distancia del valor del atributo para derivar una medicion que cuantifica el grado en el que dos puntos estan asociados espacialmente. En concreto, en los casos de atributos individuales, la informacion revelada por una medicion ISD es mas sofisticada que la que proporcionada por el indice de Moran, el indice de Moran local, y el semivariograma, pues da cuanta minuciosa de la relacion espacial y de atributo en contextos locales y globales. El concepto de ISD tambien es lo suficientemente general para ser usado en el estudio de relaciones entre multiples atributos. 本文提出了内蕴空间距离(ISD)来研究空间中任意两点之间的空间关系。ISD是考虑空间上分离的两点各自物理和属性接近度的一种距离度量。通过构造一个算法将该概念转变为ISD可度量方式。基于ISD概念，空间上的两点通过连接两者迁移路径相关联。当ISD度量减小时，两点之间空间关系变得越来越强。理论论证和实例演示表明ISD概念并不倾向于符合地理学第一定律，但直接考虑两点间物理距离和属性距离临近性的变化可以推导两点在空间上的联系程度。特别是在单一属性案例中，相比于Moran’s I,局部Moran’s I和半方差图，ISD度量揭示了全局与局部环境中详尽的空间相关信息。同时，ISD概念在研究多属性的空间关系中也是足够通用的。

Aims: To study E-cadherin and β-catenin expression in stage I adult-type granulosa cell tumours (AGCTs) and correlate the findings with tumour morphology and clinical outcome. Methods and results: The study group comprised 62 FIGO stage I AGCTs, including 48 stage IA and 14 stage IC cases. Fifty patients (80.6%) had negative clinical follow-up over periods from 3.0 to 19.2 years (median 6.4 years), and 12 patients (19.4%) developed metastases at intervals of 3.6–16.2 years (median 8.6 years). β-Catenin and E-cadherin were expressed in 62 (100%) and 53 (85%) primary tumours, respectively, and staining was more consistent and intense in areas showing sex cord-like morphology. In contrast, diffuse tumour areas often showed weak or moderate staining (β-catenin) or were negative (E-cadherin), and there was reduced expression of both proteins in luteinized cells. Reduced β-catenin expression in primary tumours correlated with increased risk of recurrence (P = 0.002) and a shorter time interval to recurrence, whereas there was no correlation between E-cadherin staining and the risk of metastases. Conclusions: Localized variations in adhesion protein expression may partly explain the diverse morphological patterns exhibited by AGCT, and reduced β-catenin staining in primary tumours may have value as an adverse prognostic factor.

Aim and objectives: This study examines the attitudes of healthcare staff and patients’ family members towards family presence during resuscitation (FPDR) in critical care units in Hong Kong. Background: A wealth of literature is available on FPDR in various hospital and healthcare settings. The findings include many anecdotal accounts of both the positive and the negative effects of family presence. There is little documentation on the comparisons of staff and family members’ perceptions and the predictors of staff attitudes towards FPDR practice. Design: Cross-sectional survey design. Method: A convenience sample of 163 healthcare staff and 69 family members was recruited from the intensive care units. Results: There was significant difference in the attitudes of healthcare staff and patients’ families towards FPDR. The regression analysis showed that the healthcare staff would be more supportive to FPDR if family members could share the dying moments with patients, family members were accompanied by a bereavement team member, there was adequate staff to support the family and staff members were adequately trained. If healthcare staff feel that family members may have the impression that the resuscitation is chaotic, witness resuscitation is traumatic experience for the family, family presence will increase risk of litigation and colleagues will not allow family members to stay during resuscitation making them less supportive of FPDR. Nurses were more supportive to FPDR than doctors. Conclusion: The results provide information for healthcare professionals on the development of FPDR programmes for patients and their family members. Through multi-disciplinary collaborations, the effective and safe implementation of FPDR practice can be enhanced. Relevance to clinical practice: The results could help the clinical staff to develop written guidelines to produce an integrated and consistent approach to this sensitive issue in clinical practice.

Stewart C J R, Leung Y C & Whitehouse A (2012) Histopathology 60, E106–E114 Fallopian tube metastases of non-gynaecological origin: a series of 20 cases emphasizing patterns of involvement including intra-epithelial spread Aims: To determine the frequency and distribution of Fallopian tube involvement in patients with ovarian metastases of non-gynaecological origin. Methods and results: All Fallopian tube tissue was processed for histological examination in a consecutive series of 31 patients with ovarian metastases of non-gynaecological origin. The most common primary sites were appendix (n = 10) colon (n = 7), stomach (n = 6) and breast (n = 4). Twenty cases (65%) showed at least one type of tubal spread. Mural involvement was most common (14 cases) but serosal, intra-vascular, intra-epithelial and intra-lumenal spread were also identified in 12, 9, 8 and 11 cases respectively. Intra-epithelial involvement was restricted to the fimbrial epithelium and mimicked tubal carcinoma in situ (CIS) architecturally. Pagetoid invasion was noted in two of the cases. Conclusions: The Fallopian tubes are commonly involved in patients who have neoplasms metastatic to the ovaries. Metastases may show a CIS-like pattern of intra-epithelial spread and therefore small serous CIS-type lesions may not represent proof of tubal tumour origin in patients who have high-stage pelvic serous carcinomas. The frequency of intra-lumenal tumour cells supports transtubal spread as a likely mechanism for mucosal involvement by metastatic tumours involving the lower genital tract.

This study proposes a theory-based cellular automata (CA) in which CA rules are constructed on the basis of a theory of urban land-use change and other local conditions. Rent gap theory that describes urban redevelopment and exogenous conditions that reflect urban development are embedded into a CA to simulate changes of land use. The theoretical framework provides a strong conceptual background for the CA simulation. A case study demonstrates the flexibility of the integrated framework for simulating land-use changes in complex settings. This research aims to help decision-makers formulate appropriate development plans. Este estudio propone un modelo de tipo automata celular (CA) en el cual las reglas CA son construidas en base a una teoria de cambio de uso del suelo urbano, asi como de otras condiciones locales. La teoria de la brecha de renta (rent gap theory), que describe la renovacion urbana y las condiciones exogenas que reflejan el desarrollo urbano es la seleccionada y es integrada al modelo CA de simulacion propuesto. Este marco teorico proporciona una base conceptual solida para la simulacion integrada de CA que es flexible y aplicable en contextos complejos. Esto queda demostrado en el estudio de caso presentado en el articulo. Los resultados de esta investigacion buscan orientar a los tomadores de decisiones hacia la formulacion de planes de desarrollo mas apropiados. 本研究提出一种基于理论的细胞自动机模型(CA),其细胞自动机规则是基于城市土地利用变化理论及其他地方性条件加以构建。描述了城市再开发的地租级差理论和反映城市发展的外生条件均被整合至CA中以模拟土地利用变化。该理论框架为CA模拟提供了强有力的概念背景，案例分析显示了该整合框架在复杂设置条件下模拟土地利用变化的灵活性。本研究旨在帮助决策者制定合适的发展规划。

Imprecision of regional boundaries is subjected to a formal analysis within a fuzzy set theoretic framework. Regions are characterized by linguistic propositions which have precise mathematical translations. It is demonstrated that boundaries are generally fuzzy and exist as gradients rather than lines. Similarly, regions overlap to a certain extent. Though regional characterizations are imprecise, the extent of a fuzzy boundary can be exactly demarcated. Concepts of regional cores and edges are also examined. A simple climatic classification problem is employed to illustrate the theoretical arguments. The framework appears to be more natural, informative, and flexible. It comprises the conventional regional concepts as special cases.

Aims. The aim of this study is to determine the effectiveness of a diabetes nurse clinic intervention in controlling the poor glycaemia of older patients with type 2 diabetes. Research method. This is a quasi-experimental design with pre- and follow-up tests. The study was conducted in a regional acute hospital in Hong Kong. A total of 150 (75 controls, 75 cases) poor glycaemic control older patients with diabetes were recruited in the study. Outcome measures. Biomedical and psychological data were collected at pre- and follow-up period and compared between groups. Results. The study results show an effective intervention of diabetes nurse clinic in giving consultation and education to the type 2 diabetic patients. Subjects in the nurse follow-up group showed an improvement in the HbA1c, and systolic blood pressure and reduction on healthcare utilization. Conclusion. The study provided evidence to support the diabetes nurse clinic in treating the older patients with diabetes. This study has provided confidence to the diabetes nurse to treat the unstable older patients with diabetes. Relevance to clinical practice. Diabetes mellitus is a serious health concern that most commonly affects older people. As indicated by the results of this study, this educational programme can act as an effective nursing intervention to the type 2 diabetic patients.

In a world bewildered by spectacular advances in imaging technology, the early detection of an abdominal pregnancy should be a feasible objective. A case of an advanced abdominal pregnancy is presented. Although the pregnancy was the result of in vitro fertilisation technology, the diagnosis was not suspected until 35 weeks gestation. Both ultrasound and magnetic resonance imaging (MRI) were used to achieve a diagnosis prior to delivery. The placenta was left within the peritoneal cavity but removal was necessitated for maternal symptomatology 4 months postdelivery. This case illustrates that despite the almost ubiquitous usage of prenatal ultrasound, extrauterine pregnancies may not be detected in a timely manner unless attention to basic ultrasound techniques is followed.

A state-of-the-art discussion of the fuzzy set theoretic spatial analysis is provided in this paper. Regional concepts and regionalisation, spatial preference-utilitychoice structures, spatial equilibrium, and optimal spatial planning are among the basic issues analysed. Due to imperfect information, systems complexity, and vague cognitive and decisionmaking processes, the conventional two-valued mathematical system appears to be too rigid and less natural in modelling spatial structures and processes. It is demonstrated that fuzzy sets theoretic notions often generalise conventional spatial concepts and provide new perspectives for analysing both static and dynamic spatial systems.

Asthma is associated with abnormal airway smooth muscle (ASM) growth that may contribute to airway narrowing and hyperresponsiveness. We investigated the role of mitogen-activated protein kinase (MAPK) pathway in IL-1β induced ASM proliferation in the rat. Rat tracheal ASM cells were dissociated and maintained in culture. We examined the effect of selective MAPK inhibitors, SB239063 (a p38 MAPK inhibitor), U0126 (a mitogen-activated and extracellular regulated kinase kinase, MEK-1, inhibitor which inhibits downstream extracellular regulated kinase, ERK, activity), and SP600125 (a c-jun N-terminal kinase, JNK, inhibitor) on IL-1β-induced proliferation. Proliferation of ASM cells was significantly increased following exposure to IL-1β in a dose-dependent manner. p38, JNK and ERK MAPKs were activated by IL-1β in a time-dependent manner, with peak activation time at 30, 60 min and at 6 h, respectively. This activation was inhibited by their respective inhibitors. SP600125 (20 μM) had no effect on IL-1β-induced ERK and p38 phosphorylation. SB239063, U0126 and SP600125 dose-dependently inhibited IL-1β-dependent proliferation at doses that inhibit the activities of p38, ERK and JNK MAPKs, respectively. No additive or synergistic effects were observed on proliferative responses with any combination of these compounds. In conclusion, the three major MAPK pathways, ERK as well as the p38 MAPK and JNK pathways, are independent regulators of IL-1β-dependent proliferation of rat ASM. British Journal of Pharmacology (2004) 143, 1042–1049. doi:10.1038/sj.bjp.0705971

Chronic cellular inflammation and airway wall remodelling with subepithelial fibrosis and airway smooth muscle (ASM) cell hyperplasia are features of chronic asthma. Jun N-terminal kinase (JNK) may be implicated in these processes by regulating the transcriptional activity of activator protein (AP)-1. We examined the effects of an inhibitor of JNK, SP600125 (anthra [1,9-cd] pyrazole-6 (2 H)-one), in a model of chronic allergic inflammation in the rat. Rats sensitised to ovalbumin (OA) were exposed to OA-aerosol every third day on six occasions and were treated with SP600125 (30 mg kg−1 b.i.d; 360 mg in total) for 12 days, starting after the second through to the sixth OA exposure. We measured eosinophilic and T-cell inflammation in the airways, proliferation of ASM cells and epithelial cells by incorporation of bromodeoxyuridine (BrdU), and bronchial responsiveness to acetylcholine. SP600125 significantly reduced the number of eosinophils (P