Breast cancer and cytomegalovirus.

PURPOSE: To determine whether cytomegalovirus is causally associated with breast cancer and whether cytomegalovirus should be categorised as an oncogenic virus. METHODS: We undertook a review of published epidemiological and laboratory studies, using established causal criteria: Bradford Hill criteria to determine whether cytomegalovirus is associated with breast cancer; and Evans/Mueller criteria to determine whether cytomegalovirus should be categorised as an oncogenic virus. RESULTS: Although there are inconsistencies in the findings of published epidemiological and laboratory studies, these may be explained by factors such as: differences in timing of blood samples, differences in selection of cases and controls, or high cytomegalovirus seroprevalence among participants in the epidemiological studies; and, in the laboratory studies, differences in sample preparations, age of sample, whether or not paired breast cancer and normal breast tissue samples were used, differences in the tests, primers and/or antibodies used, differences in histological types of breast cancer studied, and/or features of the virus. CONCLUSIONS: Overall, the results of published studies of cytomegalovirus and breast cancer suggest cytomegalovirus is a causal factor for at least some types of breast cancer. If the evidence for a link between cytomegalovirus and breast cancer continues to strengthen, further research could lead to: targeted screening; therapy using antiviral drugs; and, perhaps, primary prevention of a significant proportion of breast cancer. Vaccination against viruses has already been shown to be effective in preventing cervix and liver cancer; cytomegalovirus vaccines are already under development.

Successful Heart-Lung Transplant for a Patient on Continuous-Flow Left Ventricular Assist Device Support Complicated With Amiodarone-Induced Pulmonary Fibrosis.

In this case report, we present a successful case of en bloc heart-lung transplant in a patient with advanced cardiopulmonary respiratory failure from amiodarone-associated pulmonary fibrosis that occurred post-left ventricular assist device implantation.

Successful Outcome Following Orthotopic Heart Transplantation With a Donor Half Way Across The Country.

Orthotopic heart transplantation is the criterion standard treatment for end-stage heart failure and the number of recipient candidates has been increasing. Despite this increasing demand, there is limited donor organ supply. In order to surmount this challenge, we propose harvesting donor hearts from more distant locations and accepting longer cold ischemic times. The usual accepted total ischemic time limit for the transplanted human heart is up to 4 hours. Here, we report the successful use of a donor heart from 1268 miles away with a total allograft ischemic time greater than 6 hours.

Comparison of multi-institutional pre-treatment verification for VMAT of nasopharynx with delivery errors.

PURPOSE: Measurement-based pre-treatment verification with phantoms frequently uses gamma analysis to assess acceptable delivery accuracy. This study evaluates the sensitivity of a commercial system to simulated machine errors for three different institutions' Volumetric Modulated Arc Therapy (VMAT) planning approaches. METHODS: VMAT plans were generated for ten patients at three institutions using each institution's own protocol (manually-planned at institution 1; auto-planned at institutions 2 and 3). Errors in Multi-Leaf Collimator (MLC) field size (FS), MLC shift (S), and collimator angle (C) of -5, -2, -1, 1, 2 and 5 mm or degrees were introduced. Dose metric constraints discriminated which error magnitudes were considered unacceptable. The smallest magnitude error treatment plans deemed clinically unacceptable (typically for a 5% dose change) were delivered to the ArcCHECK for all institutions, and with a high-dose point ion chamber measurement in 2 institutions. Error detection for different gamma analysis criteria was compared. RESULTS: Not all deliberately introduced VMAT plan errors were detected using a typical 3D 3%/3 mm global gamma pass rate of 95%. Considering all institutions, gamma analysis was least sensitive to negative FS errors. The most sensitive was a 2%/2 mm global analysis for institution 1, whilst for institution 2 it was 3%/3 mm global analysis. The majority of errors (58/59 for institution 1, 54/60 for institution 3) were detected using ArcCHECK and ion chamber measurements combined. CONCLUSIONS: Not all clinically unacceptable errors are detected. Combining ion chamber measurements with gamma analysis improved sensitivity and is recommended. Optimum gamma settings varied across institutions.

Optical polarization of excitons and trions under continuous and pulsed excitation in single layers of WSe2.

The potential for valleytronic operation has stimulated much interest in studying polarized emission from transition metal dichalcogenides. In most studies, however, little regard is given to the character of laser excitation. We measure the circularly polarized photoluminescence of WSe2 monolayers as a function of excitation energy for both continuous-wave (cw) and pulsed laser excitation sources. Using cw excitation, the temperature dependence of the depolarization of the trion follows the same trend as that of the neutral exciton and involves collisional broadening. However, the polarization of the trion is nearly twice the polarization of the neutral exciton at low temperatures. When a pulsed laser with the same average fluence is used as the excitation source, the degrees of polarization become very similar, in stark contrast to the cw results. The difference in polarization behaviors is linked to the different amounts of energy deposited in the system during these measurements for similar average fluences. At a moderate fluence, pulsed excitation also has the potential to fundamentally alter the emission characteristics of WSe2.

Optical polarization and intervalley scattering in single layers of MoS2 and MoSe2.

Single layers of MoS2 and MoSe2 were optically pumped with circularly polarized light and an appreciable polarization was initialized as the pump energy was varied. The circular polarization of the emitted photoluminescence was monitored as a function of the difference between the excitation energy and the A-exciton emission at the K-point of the Brillouin zone. Our results show a threshold of twice the LA phonon energy, specific to the material, above which phonon-assisted intervalley scattering causes depolarization. In both materials this leads to almost complete depolarization within ~100 meV above the threshold energy. We identify the extra kinetic energy of the exciton (independent of whether it is neutral or charged) as the key parameter for presenting a unifying picture of the depolarization process.

Translating colorectal cancer genetics into clinically useful biomarkers.

Colorectal cancer (CRC) is a major health problem worldwide accounting for over a million deaths annually. While many patients with Stage II and III CRC can be cured with combinations of surgery, radiotherapy and chemotherapy, this is morbid costly treatment and a significant proportion will suffer recurrence and eventually die of CRC. Increased understanding of the molecular pathogenesis of CRC has the potential to identify high risk patients and target therapy more appropriately. Despite increased understanding of the molecular events underlying CRC development, established molecular techniques have only produced a limited number of biomarkers suitable for use in routine clinical practice to predict risk, prognosis and response to treatment. Recent rapid technological developments, however, have made genomic sequencing of CRC more economical and efficient, creating potential for the discovery of genetic biomarkers that have greater diagnostic, prognostic and therapeutic capabilities for the management of CRC. This paper reviews the current understanding of the molecular pathogenesis of CRC, and summarizes molecular biomarkers that surgeons will encounter in current clinical use as well as those under development in clinical and preclinical trials. New molecular technologies are reviewed together with their potential impact on the understanding of the molecular pathogenesis of CRC and their potential clinical utility in classification, diagnosis, prognosis and targeting of therapy.

Anomalous temperature-dependent spin-valley polarization in monolayer WS2.

Single layers of transition metal dichalcogenides (TMDs) are direct gap semiconductors with nondegenerate valley indices. An intriguing possibility for these materials is the use of their valley index as an alternate state variable. Several limitations to such a utility include strong intervalley scattering, as well as multiparticle interactions leading to multiple emission channels. We prepare single-layer WS2 films such that the photoluminescence is from either the neutral or charged exciton (trion). After excitation with circularly polarized light, the neutral exciton emission has zero polarization. However, the trion emission has a large polarization (28%) at room temperature. The trion emission also has a unique, non-monotonic temperature dependence that is a consequence of the multiparticle nature of the trion. This temperature dependence enables us to determine that intervalley scattering, electron-hole radiative recombination, and Auger processes are the dominant mechanisms at work in this system. Because this dependence involves trion systems, one can use gate voltages to modulate the polarization (or intensity) emitted from TMD structures.

The impact of abdominal pain on global measures in patients with chronic idiopathic constipation, before and after treatment with linaclotide: a pooled analysis of two randomised, double-blind, placebo-controlled, phase 3 trials.

BACKGROUND: Few clinical trials in chronic idiopathic constipation (CIC) patients have evaluated abdominal symptom severity and whether CIC patients with abdominal symptoms respond similarly to patients with limited abdominal symptoms. AIMS: To examine abdominal symptom severity and relationships between symptoms and global measures at baseline; compare linaclotide's effect on symptoms in subpopulations with more or less abdominal pain; and assess relationships between symptom improvement and global measures in these two subpopulations. METHODS: In two phase 3 trials, patients meeting modified Rome II CIC criteria were assigned to linaclotide 145 µg, 290 µg, or placebo once daily. Patients rated abdominal and bowel symptoms daily during 2-week pre-treatment and 12-week treatment periods. Linaclotide's effect on symptoms and global measures [constipation severity, health-related quality of life (HRQOL), treatment satisfaction] and their inter-relationships were assessed in post hoc analyses of abdominal pain subpopulations. RESULTS: Of 1271 CIC patients, 23%, 32%, and 43% reported moderate-to-severe abdominal pain, discomfort, and bloating, respectively, during baseline. In more-severe abdominal pain patients, abdominal symptoms were more strongly correlated than bowel symptoms with global measures, but in less-severe abdominal pain patients, abdominal and bowel symptoms were similarly correlated with global measures, at baseline and post-treatment. Linaclotide significantly improved all symptoms and global measures in both subpopulations. CONCLUSIONS: When abdominal pain is present in CIC, abdominal and not bowel symptoms may drive patient assessments of constipation severity, HRQOL, and treatment satisfaction. Linaclotide (145 µg and 290 µg) is an effective treatment for both abdominal and bowel symptoms, even in CIC patients with more severe abdominal pain at baseline. (Clinicaltrials.gov: NCT00765882, NCT00730015).

Responders vs clinical response: a critical analysis of data from linaclotide phase 3 clinical trials in IBS-C.

BACKGROUND: US Food and Drug Administration (FDA) set a rigorous standard for defining patient responders in irritable bowel syndrome-C (IBS-C; i.e., FDA's Responder Endpoint) for regulatory approval. However, this endpoint's utility for health-care practitioners to assess clinical response has not been determined. We analyzed pooled IBS-C linaclotide trial data to evaluate clinically significant responses in linaclotide-treated patients who did not meet the FDA responder definition. METHODS: Percentages of FDA non-responders reporting improvement in abdominal pain, bowel function and/or global relief measures were determined using pooled data from two linaclotide Phase 3 IBS-C trials. KEY RESULTS: 1602 IBS-C patients enrolled; 34% of linaclotide-treated and 17% of placebo-treated patients met the FDA Responder Endpoint (p < 0.0001). Among FDA non-responders at week 12, 63% of linaclotide-treated patients reported their abdominal pain was at least somewhat relieved, compared with 48% of placebo-treated patients. For stool frequency, 62% of linaclotide-treated patients reported that they were at least somewhat improved at week 12, compared with 46% of placebo-treated patients. For global IBS symptoms, 65% of linaclotide-treated patients reported at least some IBS-symptom relief, 43% reported adequate relief of IBS symptoms, and 57% reported being satisfied with linaclotide treatment, vs placebo rates of 48%, 34%, and 41% respectively. CONCLUSIONS & INFERENCES: Most linaclotide-treated IBS-C patients who were FDA non-responders reported some improvement in abdominal pain and stool frequency, and global relief/satisfaction. In addition to the FDA Responder Endpoint, differing response thresholds and symptom-specific change from baseline should be considered by clinicians for a complete understanding of clinical response to linaclotide and other IBS-C therapies.

An evaluation of the FDA responder endpoint for IBS-C clinical trials: analysis of data from linaclotide Phase 3 clinical trials.

BACKGROUND: Our objective was to evaluate the performance of the Food and Drug Administration (FDA) Responder Endpoint for clinical trials in IBS-C, using data from two large Phase 3 clinical trials of linaclotide. The FDA interim endpoint requires that, for 50% of trial weeks, patients report ≥30% decrease in Abdominal Pain at its worst and (in the same week) an increase in Complete Spontaneous Bowel Movements (CSBMs) of ≥1 from baseline. METHODS: Anchor-based methodology was used to estimate thresholds of clinically meaningful change using symptom-specific patient rating of change questions (PRCQs) and symptom severity questions. The diagnostic accuracy of the FDA Responder Endpoint was assessed using sensitivity/specificity-based methods. KEY RESULTS: Using anchor-based methods, the estimates of the clinically meaningful improvement thresholds for Abdominal Pain ranged from 25.9% to 32.4% and thresholds for increase in weekly CSBM rate ranged from 1.4 to 1.6 CSBMs per week. Compared with the symptom-specific PRCQs for patient rating of relief, the FDA Responder Endpoint has a sensitivity of 60.7%, a specificity of 93.5%, and an accuracy of 82.0%. Changing the number of weeks required to be a responder or the percentage improvement in the Abdominal Pain criteria did not result in notable improvement in the accuracy of the FDA Responder Endpoint. CONCLUSIONS & INFERENCES: The FDA Responder Endpoint for IBS-C clinical trials represents clinically meaningful improvements in IBS-C symptoms for patients with excellent specificity and reasonable sensitivity.

Randomised clinical trials: linaclotide phase 3 studies in IBS-C - a prespecified further analysis based on European Medicines Agency-specified endpoints.

BACKGROUND: Treatment options that improve overall symptoms of irritable bowel syndrome with constipation (IBS-C) are lacking. AIM: A prespecified further analysis to evaluate the efficacy and safety of linaclotide, a guanylate cyclase C agonist, in patients with IBS-C, based on efficacy parameters prespecified for European Medicines Agency (EMA) submission. METHODS: Two randomised, double-blind, multicentre Phase 3 trials investigated once-daily linaclotide (290 µg) for 12 weeks (Trial 31) or 26 weeks (Trial 302) in patients with IBS-C. Prespecified primary endpoints were the EMA-recommended co-primary endpoints: (i) 12-week abdominal pain/discomfort responders [≥30% reduction in mean abdominal pain and/or discomfort score (11-point scales), with neither worsening from baseline, for ≥6 weeks] and (ii) 12-week IBS degree-of-relief responders (symptoms 'considerably' or 'completely' relieved for ≥6 weeks). RESULTS: Overall, 803 (Trial 31) and 805 patients (Trial 302) were randomised. A significantly greater proportion of linaclotide-treated vs. placebo-treated patients were 12-week abdominal pain/discomfort responders (Trial 31: 54.8% vs. 41.8%; Trial 302: 54.1% vs. 38.5%; P < 0.001) and IBS degree-of-relief responders (Trial 31: 37.0% vs. 18.5%; Trial 302: 39.4% vs. 16.6%; P < 0.0001). Similarly, significantly more linaclotide- vs. placebo-treated patients were responders for ≥13 weeks in Trial 302 (abdominal pain/discomfort: 53.6% vs. 36.0%; IBS degree-of-relief: 37.2% vs. 16.9%; P < 0.0001). The proportion of sustained responders (co-primary endpoint responders plus responders for ≥2 of the last 4 weeks of treatment) was also significantly greater with linaclotide vs. placebo in both trials (P < 0.001). CONCLUSION: Linaclotide treatment significantly improved abdominal pain/discomfort and degree-of-relief of IBS-C symptoms compared with placebo over 12 and 26 weeks. TRIAL REGISTRATION: ClinicalTrials.gov (identifiers: NCT00948818 and NCT00938717).

Evaluation of physician assistants in National Health Service Scotland.

Physician assistants (PAs) have medical training and work supervised by a doctor. In 2006-2008 the Scottish Government piloted use of USA-trained PAs. The aim of the paper is to evaluate the impact and contribution made by PAs to delivering effective health care in National Health Service (NHS) Scotland. Mixed methods, longitudinally, including interviews, feedback forms and activity data collection. Data analysis used nVivo, SPSS and Excel. Participants were 15 USA-trained PAs, medical supervisors and team members, 20 patients, four NHS senior managers and three trade union representatives. Settings were four Scottish NHS Boards where PAs worked in primary care, out of hours clinics, emergency medicine, intermediate care and orthopaedics. Two minor patient safety issues arose. Patients were satisfied with PAs. Scope of practice did not replicate US working. Inability to prescribe was a hindrance. PAs tended to have longer consultations, but provided continuity and an educational resource. They were assessed to be mid-level practitioners approximating to nurse practitioner or generalist doctor. Valued features were generalism, medical background, confidence differential diagnosis and communication. Interviewees suggested PAs could fulfil roles currently filled by medical staff, potentially saving resources. In conclusion, there is potential for PAs to fulfil distinctive mid-level roles in the Scottish NHS adding value in continuity, communication and medical approach.

Association of angiopoietin-2, C-reactive protein and markers of obesity and insulin resistance with survival outcome in colorectal cancer.

BACKGROUND: This study investigated the relationship of obesity, insulin resistance, inflammation and angiogenesis with cancer progression and survival in a colorectal cancer cohort. METHODS: Clinical and pathological data, along with anthropometric and follow-up data, were collected from 344 consecutive colorectal cancer patients. Serum samples at diagnosis were analysed by immunoassay for adiponectin, C-reactive protein (CRP), vascular endothelial growth factor-A (VEGF-A), angiopoietin-2 (Ang-2), insulin-like growth factor-1 (IGF-1), insulin and C-peptide. RESULTS: Serum Ang-2 and VEGF-A levels increased with tumour T stage (P=0.007 and P=0.025, respectively) and N stage (P=0.02 and P=0.03, respectively), and correlated with CRP levels (r=0.43, P<0.001 and r=0.23, P<0.001, respectively). Angiopoietin-2 correlated with C-peptide (r=0.14, P=0.007) and VEGF-A with IGF-1 in males (r=0.25, P=0.001). Kaplan-Meier analysis showed that patients with high serum levels of CRP and Ang-2 had significantly reduced survival (both P≤0.001). After adjusting for tumour stage and age, Ang-2 remained a significant predictor of survival. The CRP levels were inversely associated with survival in American Joint Committee on Cancer stage II patients (P=0.038), suggesting that CRP could be used to support treatment decisions in this subgroup. Serum markers and anthropometric measures of obesity correlated with each other, but not with survival. CONCLUSION: Our study supports the concept that obesity-related inflammation, rather than obesity itself, is associated with colorectal cancer progression and survival. The study confirms serum Ang-2 as a predictive marker for outcome of colorectal cancer.

Bayesian estimation of weak material dispersion: theory and experiment.

This work considers the estimation of dispersion in materials via an interferometric technique. At its core, the problem involves extracting the quadratic variation in phase over a range of wavelengths based on measured optical intensity. The estimation problem becomes extremely difficult for weakly dispersive materials where the quadratic nonlinearity is very small relative to the uncertainty inherent in experiment. This work provides a means of estimating dispersion in the face of such uncertainty. Specifically, we use a Markov Chain Monte Carlo implementation of Bayesian analysis to provide both the dispersion estimate and the associated confidence interval. The interplay between various system parameters and the size of the resulting confidence interval is discussed. The approach is then applied to several different experimental samples.

Guanylate cyclase C-mediated antinociceptive effects of linaclotide in rodent models of visceral pain.

BACKGROUND Linaclotide is a novel, orally administered investigational drug currently in clinical development for the treatment of constipation-predominant irritable bowel syndrome (IBS-C) and chronic idiopathic constipation. Visceral hyperalgesia is a major pathophysiological mechanism in IBS-C. Therefore, we investigated the anti-nociceptive properties of linaclotide in rodent models of inflammatory and non-inflammatory visceral pain and determined whether these pharmacological effects are linked to the activation of guanylate cyclase C (GC-C). METHODS Orally administered linaclotide was evaluated in non-inflammatory acute partial restraint stress (PRS) and acute water avoidance stress (WAS) models in Wistar rats, and in a trinitrobenzene sulfonic acid (TNBS)-induced inflammatory model in Wistar rats and GC-C null mice. KEY RESULTS In TNBS-induced colonic allodynia, linaclotide significantly decreased the number of abdominal contractions in response to colorectal distension without affecting the colonic wall elasticity change in response to distending pressures after TNBS. However, linaclotide had no effect on visceral sensitivity under basal conditions. In addition, linaclotide significantly decreased colonic hypersensitivity in the PRS and WAS models. In wild type (wt) and GC-C null mice, the instillation of TNBS induced similar hyperalgesia and allodynia. However, in post-inflammatory conditions linaclotide significantly reduced hypersensitivity only in wt mice, but not in GC-C null mice. CONCLUSIONS & INFERENCES These findings indicate that linaclotide has potent anti-nociceptive effects in several mechanistically different rodent models of visceral hypersensitivity and that these pharmacological properties of linaclotide are exerted through the activation of the GC-C receptor. Therefore, linaclotide may be capable of decreasing abdominal pain in patients suffering from IBS-C.

Myocardial metastasis of cutaneous squamous cell carcinoma in a renal transplant recipient.

Myocardial metastasis from a cutaneous squamous cell carcinoma (SCC) is rare. Herein we have presented a case of metastasis from cutaneous SCC to the myocardium in a renal transplant recipient, which was confirmed by a cardiac fine-needle biopsy. Postmortem examination revealed disseminated metastatic disease involving myocardium, lungs, thyroid, skin, and peritoneum secondary to cutaneous SCC likely related to immunosuppression. At 46 years of age, he received a renal transplant for chronic renal failure caused by chronic glomerulonephritis. He started to develop multiple nonmelanoma skin cancers 4 years later. At least 23 invasive SCCs and 14 basal cell carcinomas were excised. His immunosuppressive regimen consisted of cyclosporine (150 mg), azathioprine (75 mg), and prednisone (10 mg daily), which was not modified despite multiple nonmelanoma skin cancers. Our case report further illustrates the potentially aggressive and fatal nature of cutaneous SCCs that can develop in organ transplant recipients. It argues for modification of the immunosuppressive regimen in such patients. The management of renal transplant patients with nonmelanoma skin cancers remains difficult and complex.

Prevalence of Mycoplasma genitalium in health clinic attendees complaining of vaginal discharge in Bangladesh.

The objective of the study was to determine the prevalence of Mycoplasma genitalium in a sample of health clinic attendees complaining of vaginal discharge. A subsample of 399 vaginal and cervical swabs was randomly selected from 2579 samples collected during a study to determine the causes of vaginal discharge in women attending primary health-care clinics in Dhaka, Bangladesh. Cervical samples were tested for M. genitalium by polymerase chain reaction. In addition, the samples were tested for Chlamydia trachomatis, Neisseria gonorrhoeae, Trichomonas vaginalis, bacterial vaginosis and candida. M. genitalium was detected in three samples (0.8%; 95% confidence interval: 0.00-1.6). The prevalence of C. trachomatis, N. gonorrhoeae T. vaginalis, bacterial vaginosis and candida was 1.3, 3.8, 8, 23.25 and 32.5%, respectively. Two women with M. genitalium were co-infected with T. vaginalis or candida. This is the first study to document the existence of M. genitalium in Bangladesh. Although the prevalence of this infection is low in the population tested, further research into this pathogen in other Bangladeshi populations is justified.

Verification of nose irradiation using orthovoltage x-ray beams.

Determination of dose distributions from superficial and orthovoltage irradiations of basal cell carcinoma of the nose has been performed using a nose shaped phantom constructed from paraffin wax. EBT type radiochromic film was used for dose measurements. A 2 cm diameter 50 kVp anterior field was used to irradiate the nose phantom, with sheets of film placed at 7 mm, 14 mm and 23 mm physical depth. The percentage depth doses at these points were measured to be 84% +/- 1.6%, 66% +/- 2.7% and 50% +/- 1.2% respectively, compared to the expected percentage depth doses of 72%, 52% and 34%, measured in full scatter conditions. This discrepancy is believed to be due to the steep drop off at the sides of the nose phantom, resulting in reduced attenuation at the edges of the beam, which in turn results in an increase in the scatter contribution to the dose at depth on the central axis. Measured dose profiles from this technique showed a reasonably uniform distribution. A second technique using a 250 kVp tangent-like field to irradiate the tip of the nose was also tested. Radiochromic film was placed against the edges of the phantom for dose measurement. The dose at the surface was measured to be 27% +/- 1.5% less than the expected dose. It is believed that this discrepancy is due to a combination of the lack of backscatter from the phantom, and a small offset between the phantom and the treatment cone. Dose measurements and profiles showed that this technique results in a variation in dose across the treated volume of 7%. However, the difficulty in predicting the delivered dose prohibited it from clinical use.

The angiogenic factor thymidine phosphorylase up-regulates the cell adhesion molecule P-selectin in human vascular endothelial cells and is associated with P-selectin expression in breast cancers.

Thymidine phosphorylase (TP) is an angiogenic enzyme, catalysing the reversible phosphorylation of thymidine to thymine and 2-deoxyribose. TP is up-regulated in neoplasia, being associated with advanced tumour stage, microvessel density and prognosis in several tumour types. Although TP is a non-mitogenic migratory factor for endothelium, the mechanism by which TP mediates these effects is still unclear. We compared the gene expression profile of endothelial cells grown in vitro in the presence or absence of TP by cDNA microarray analysis. To determine the time-course of TP angiogenic induction, endothelial cells were stimulated with TP (10 ng/ml) for 5 and 18 h. Gene expression levels of Tie2, angiopoietin (Ang)1 and Ang2, measured by RNase protection assay (RPA), showed maximal alteration at 18 h. cDNA from human umbilical vein endothelial cells (HUVEC) grown for 18 h in the presence or absence of TP (10 ng/ml) was hybridized to a human cDNA cytokine array representing 375 angiogenic genes. Significantly altered expression occurred in 89 human angiogenic genes (72 genes were up-regulated and 17 down-regulated). Changes in five genes relevant to vascular remodelling biology (Tie2, nNos, P-selectin, ephrin-B1 and TP) were validated in triplicate experiments by real-time RT-PCR. But only P-selectin gene expression remained significant. Correlation between P-selectin and TP was assessed by immunohistochemistry on 161 human breast cancers, using human tissue microarray. Tumour cell TP correlated with tumour cell P-selectin but not with endothelial cell P-selectin. These data show that TP stimulates changes in mRNA expression maximally after 18 h culture in vitro. It confirms a role for TP in vascular remodelling involving several classes of genes, including the cell adhesion molecule, P-selectin. Although confirmation of the role of TP-mediated cell adhesion molecule (CAM) induction is required; however, this pathway may provide an attractive therapeutic target, since it is likely to affect several important tumour processes, including angiogenesis and metastasis.