A coupled "AB" system: Rogue waves and modulation instabilities.

Rogue waves are unexpectedly large and localized displacements from an equilibrium position or an otherwise calm background. For the nonlinear Schrödinger (NLS) model widely used in fluid mechanics and optics, these waves can occur only when dispersion and nonlinearity are of the same sign, a regime of modulation instability. For coupled NLS equations, rogue waves will arise even if dispersion and nonlinearity are of opposite signs in each component as new regimes of modulation instability will appear in the coupled system. The same phenomenon will be demonstrated here for a coupled "AB" system, a wave-current interaction model describing baroclinic instability processes in geophysical flows. Indeed, the onset of modulation instability correlates precisely with the existence criterion for rogue waves for this system. Transitions from "elevation" rogue waves to "depression" rogue waves are elucidated analytically. The dispersion relation as a polynomial of the fourth order may possess double pairs of complex roots, leading to multiple configurations of rogue waves for a given set of input parameters. For special parameter regimes, the dispersion relation reduces to a cubic polynomial, allowing the existence criterion for rogue waves to be computed explicitly. Numerical tests correlating modulation instability and evolution of rogue waves were conducted.

On strongly interacting internal waves in a rotating ocean and coupled Ostrovsky equations.

In the weakly nonlinear limit, oceanic internal solitary waves for a single linear long wave mode are described by the KdV equation, extended to the Ostrovsky equation in the presence of background rotation. In this paper we consider the scenario when two different linear long wave modes have nearly coincident phase speeds and show that the appropriate model is a system of two coupled Ostrovsky equations. These are systematically derived for a density-stratified ocean. Some preliminary numerical simulations are reported which show that, in the generic case, initial solitary-like waves are destroyed and replaced by two coupled nonlinear wave packets, being the counterpart of the same phenomenon in the single Ostrovsky equation.

A phase II study of sunitinib in patients with recurrent epithelial ovarian and primary peritoneal carcinoma: an NCIC Clinical Trials Group Study.

PURPOSE: Sunitinib is a multitargeted receptor tyrosine kinase inhibitor. We conducted a two-stage phase II study to evaluate the objective response rate of oral sunitinib in recurrent epithelial ovarian cancer. PATIENTS AND METHODS: Eligibility required measurable disease and one or two prior chemotherapies, at least one platinum based. Platinum-sensitive or -resistant disease was allowed. Initial dose schedule was sunitinib 50 mg daily, 4 of 6 weeks. Observation of fluid accumulations during off-treatment periods resulted in adoption of continuous 37.5 mg daily dosing in the second stage of accrual. RESULTS: Of 30 eligible patients, most had serous histology (67%), were platinum sensitive (73%) and had two prior chemotherapies (60%). One partial response (3.3%) and three CA125 responses (10%) were observed, all in platinum-sensitive patients using intermittent dosing. Sixteen (53%) had stable disease. Five had >30% decrease in measurable disease. Overall median progression-free survival was 4.1 months. Common adverse events included fatigue, gastrointestinal symptoms, hand-foot syndrome and hypertension. No gastrointestinal perforation occurred. CONCLUSIONS: Single-agent sunitinib has modest activity in recurrent platinum-sensitive ovarian cancer, but only at the 50 mg intermittent dose schedule, suggesting that dose and schedule may be vital considerations in further evaluation of sunitinib in this cancer setting.

Identification of a specific interleukin 1 inhibitor in the urine of febrile patients.

The urine of febrile patients has been found to contain high concentrations of an inhibitor of interleukin 1 (IL-1)-induced thymocyte proliferation. The inhibitor is specific for IL-1 and does not block the effects of interleukin 2 (IL-2) or phytohemagglutin (PHA) on thymocytes, and it is not nonspecifically toxic for these cells. IL-1 inhibitor can be found in the urine of normal individuals and afebrile patients, but is present in increased concentrations in the urine of patients with fever of diverse etiologies. Preliminary physicochemical characterization indicates that the inhibitor is a 20-40-kdalton protein.

A phase II study of erlotinib (OSI-774) given in combination with carboplatin in patients with recurrent epithelial ovarian cancer (NCIC CTG IND.149).

OBJECTIVES: Approximately 50% of ovarian cancers have elevated levels of epidermal growth factor receptor (EGFR) which correlates with a poor prognosis. Preclinical evidence suggests that EGFR tyrosine kinase inhibitors (TKIs), such as erlotinib (OSI-774), may potentiate the anti-tumour effects of cytotoxic agents, including carboplatin. Blocking EGFR could thus potentially reverse drug resistance. The primary objective of the study was to assess the response rate to the addition of erlotinib in patients with recurrent ovarian cancer who were receiving carboplatin. METHODS: Patients enrolled on this study had either local or advanced recurrent ovarian cancer with measurable disease. They may have had up to 2 prior chemotherapy regimens, one of which must have contained platinum, and they must have responded to prior platinum therapy. Patients were stratified by platinum sensitivity and were treated with erlotinib 150 mg daily on a continuous dosing schedule, and carboplatin at an AUC of 5 every 21 days. RESULTS: Fifty patients with recurrent ovarian cancer entered the study, 33 in the platinum-sensitive arm and 17 in the platinum-resistant arm. Of patients evaluable for response, there were 14 partial responses (PR) of 30 evaluable for response (57% objective response rate (ORR)) in the platinum-sensitive arm, and 1 PR of 14 evaluable for response (7% ORR) in the platinum-resistant arm. CONCLUSIONS: The combination of erlotinib and carboplatin was active in patients with platinum-sensitive disease, but not in platinum-resistant disease. The toxicities seen were those expected with carboplatin and erlotinib.

Generation of solitons and breathers in the extended Korteweg-de Vries equation with positive cubic nonlinearity.

The initial-value problem for box-like initial disturbances is studied within the framework of an extended Korteweg-de Vries equation with both quadratic and cubic nonlinear terms, also known as the Gardner equation, for the case when the cubic nonlinear coefficient has the same sign as the linear dispersion coefficient. The discrete spectrum of the associated scattering problem is found, which is used to describe the asymptotic solution of the initial-value problem. It is found that while initial disturbances of the same sign as the quadratic nonlinear coefficient result in generation of only solitons, the case of the opposite polarity of the initial disturbance has a variety of possible outcomes. In this case solitons of different polarities as well as breathers may occur. The bifurcation point when two eigenvalues corresponding to solitons merge to the eigenvalues associated with breathers is considered in more detail. Direct numerical simulations show that breathers and soliton pairs of different polarities can appear from a simple box-like initial disturbance.

Generation of nonlinear internal waves by flow over topography: Rotational effects.

We use the forced Ostrovsky equation to investigate the generation of internal waves excited by a constant background current flowing over localized topography in the presence of background rotation. As is now well known in the absence of background rotation, the evolution scenarios fall into three cases, namely subcritical, transcritical, and supercritical. Here an analysis of the linearized response divides the waves into steady and unsteady waves. In all three cases, steady waves occur downstream but no steady waves can occur upstream, while unsteady waves can arise upstream only when there is a negative minimum of the group velocity. The regions occupied by the steady and unsteady waves are determined by their respective group velocities. When the background current is increased, the wave number of the steady waves decreases. In addition, the concavity (canyon or sill), the topographic width, and the relative strength of the rotation play an important role in the generation mechanism. Nonlinear effects modulate the wave amplitude and lead to the emergence of coherent wave packets. All these findings are confirmed by numerical simulations.

Value of targeting at-risk populations at outreach venues: findings from a local sauna.

An assessment of the need to increase access to an outreach venue, the local sauna in Walsall, UK, frequented only by men who have sex with men, was undertaken. A case-notes review of the clients who attended the monthly outreach sessions at the sauna in the year 2007 was performed. Among the 287 men seen at the 12 outreach sessions, 37% had a sexually transmitted infection (STI). Of those tested positive, 88% had never had a previous STI. Twenty-one men had syphilis and a further six tested positive for HIV. Hepatitis B vaccination was completed for 41% of the clients seen. Those who tested positive for an STI said they would not have attended a conventional setting but accepted screening at the sauna. This confirmed the need to increase access at this outreach venue, and further funding has now been provided to have outreach sessions twice a month.

Randomized intergroup trial of cisplatin-paclitaxel versus cisplatin-cyclophosphamide in women with advanced epithelial ovarian cancer: three-year results.

BACKGROUND: A randomized trial conducted by the Gynecologic Oncology Group (GOG, study #111) in the United States showed a better outcome for patients with advanced ovarian cancer on the paclitaxel-cisplatin regimen than for those on a standard cyclophosphamide-cisplatin regimen. Before considering the paclitaxel-cisplatin regimen as the new "standard," a group of European and Canadian investigators planned a confirmatory phase III trial. METHODS: This intergroup trial recruited 680 patients with broader selection criteria than the GOG #111 study and administered paclitaxel as a 3-hour instead of a 24-hour infusion; progression-free survival was the primary end point. Patient survival was analyzed by use of the Kaplan-Meier technique. Treatment effects on patient survival were estimated by Cox proportional hazards regression models. All statistical tests were two-sided. RESULTS: The overall clinical response rate was 59% in the paclitaxel group and 45% in the cyclophosphamide group; the complete clinical remission rates were 41% and 27%, respectively; both differences were statistically significant (P =.01 for both). At a median follow-up of 38.5 months and despite a high rate of crossover (48%) from the cyclophosphamide arm to the paclitaxel arm at first detection of progression of disease, a longer progression-free survival (log-rank P =.0005; median of 15.5 months versus 11.5 months) and a longer overall survival (log-rank P =. 0016; median of 35.6 months versus 25.8 months) were seen in the paclitaxel regimen compared with the cyclophosphamide regimen. CONCLUSIONS: There is strong and confirmatory evidence from two large randomized phase III trials to support paclitaxel-cisplatin as the new standard regimen for treatment of patients with advanced ovarian cancer.

Idoxifene antagonizes estradiol-dependent MCF-7 breast cancer xenograft growth through sustained induction of apoptosis.

Idoxifene is a novel selective estrogen (E2) receptor (ER) modulator that is currently in clinical development for the treatment of breast cancer. Compared to tamoxifen, idoxifene is metabolically more stable, with a higher relative binding affinity for the ER and reduced agonist activity on breast and uterine cells. Idoxifene also inhibits calmodulin, a calcium-binding protein that is involved in cell signal transduction pathways. In this study, the abilities of idoxifene and tamoxifen to antagonize E2-dependent MCF-7 xenograft growth in oophorectomized athymic mice were compared. The basis for idoxifene's antitumor activity was examined by comparing the effectiveness of the clinically used transisomer (referred to here as idoxifene) with its cis-isomer, which has a 50-fold lower relative binding affinity for ER than idoxifene but similar calmodulin-inhibitory activity. Changes in tumor cell proliferation, apoptosis, and ER-dependent protein expression were studied. Both idoxifene and tamoxifen significantly inhibited E2-dependent tumor growth, whereas cis-idoxifene had little effect. Withdrawal of E2 support induced significant tumor regression due to impaired cell proliferation (Ki-67 score, 9 versus 51% compared to E2 controls) and induction of apoptosis (3.6 versus 0.9% compared to E2 controls). Both anti-E2s inhibited cell proliferation and caused a significant 3-fold induction of apoptosis in E2 supported tumors after 1 week, which was maintained for 3 months with idoxifene (3.1 versus 0.48% compared to E2 controls) but decreased back to baseline in tumors treated with tamoxifen (0.69%). In contrast, cis-idoxifene had no effect on either cell proliferation or apoptosis. Both tamoxifen and idoxifene initially induced ER expression, whereas prolonged therapy with tamoxifen significantly reduced progesterone receptor levels. In conclusion, idoxifene resulted in similar inhibition of E2-dependent MCF-7 xenograft growth compared with tamoxifen, an effect that is mediated via ER rather than through calmodulin. Sustained induction of apoptosis may contribute to prolonged antagonism of E2-dependent growth, and it occurred to a greater extent following 3 months of idoxifene, compared to tamoxifen.

Caloric restriction leads to regional specialisation of adipocyte function in the rat.

The study analysed the responses of three metabolic parameters in five distinct adipose tissue depots to caloric restriction (4 weeks) in the rat. The aims were to evaluate whether specific adipose tissue depots were recruited for triacylglycerol (TAG) storage and/or mobilisation, and to determine to what extent specific adipose tissue depots exhibited preferences for the source of fatty acid (FA) for TAG storage. Caloric restriction led to a general enhancement of the response of lipoprotein lipase (LPL), FA synthesis and glucose utilisation to a meal. Effects were particularly marked in the parametrial, perirenal and interscapular depots compared with mesenteric and subcutaneous depots. There was no evidence that individual depots selectively expressed a preference for the pathways concerned with the generation of FA for storage (the exogenous (LPL) and the endogenous (synthesis) pathway). However, the temporal sequence of activation of these pathways differed in a manner consistent with a switch from preponderant use of FA produced via de novo synthesis during the very early phase of feeding towards later use of FA derived from circulating TAG. The overall excursions in insulin levels observed in the calorie-restricted rats were comparable to those found in free-feeding rats, but the magnitude and the rapidity of the individual metabolic responses of the adipocyte were augmented. The data are consistent with a general enhancement of insulin sensitivity and responsiveness in adipose tissue of calorie-restricted rats, together with adaptive regional specialisation of adipocyte function. These adaptations would be predicted to facilitate the immediate conservation of dietary nutrients by promoting their storage as the FA or glycerol moieties of adipose tissue TAG and thereby to ensure the regulated release of FA and glycerol from adipose tissue in accordance with the requirement for glucose conservation and/or production.

Randomized phase II study of two schedules of topotecan in previously treated patients with ovarian cancer: a National Cancer Institute of Canada Clinical Trials Group study.

PURPOSE: As topotecan is S-phase-specific, its efficacy is likely schedule-dependent. Therefore, a randomized study using a "pick the winner" design was undertaken to compare two schedules in patients with recurrent ovarian cancer. PATIENTS AND METHODS: Patients with recurrent epithelial ovarian cancer previously treated with no more than two separate regimens of chemotherapy, one of which had to be platinum-containing, were randomized to either topotecan 1.5 mg/m2 intravenously (i.v.) over 30 minutes daily for 5 days repeated every 21 days (arm A, the standard arm), or topotecan 1.75 mg/m2 as a 24-hour infusion once a week for 4 weeks repeated every 6 weeks (arm B, the experimental arm). RESULTS: Sixty-six patients were eligible and 63 were assessable for response. The response rate in arm A was 22.6% (95% confidence interval [CI], 9.6% to 41.2%), which was significantly superior to that in arm B, 3.1% (95% CI, 0.1% to 16%) (P = .026). The regimens were not equitoxic, with 94% of patients on arm A experiencing grade 3 or 4 granulocytopenia as opposed to 52% on arm B. CONCLUSION: The weekly 24 hour infusion of topotecan at 1.75 mg/m2 was ineffective in relapsed ovarian cancer. The daily-times-five schedule remains the schedule of choice. As the regimens were not equitoxic, one cannot differentiate between an ineffective schedule and an ineffective dose as the reason for the differing response rates. However, the degree of myelotoxicity that already occurs will preclude any substantially higher dosing with the weekly regimen.

Phase II feasibility study of sequential couplets of Cisplatin/Topotecan followed by paclitaxel/cisplatin as primary treatment for advanced epithelial ovarian cancer: a National Cancer Institute of Canada Clinical Trials Group Study.

PURPOSE: Despite the improved results in advanced ovarian cancer achieved with the addition of paclitaxel to frontline therapy, there remains room for improvement. One approach is to add new agents such as topotecan. Because myelosuppression limits the delivery of topotecan with paclitaxel/cisplatin in a three-drug combination, we explored giving sequential couplets of cisplatin/topotecan followed by paclitaxel/cisplatin. PATIENTS AND METHODS: Forty-four patients with residual epithelial ovarian carcinoma after primary surgery were studied. Cisplatin 50 mg/m(2) on day 1 and topotecan 0.75 mg/m(2) on days 1 through 5 were administered at 21-day intervals for four cycles, followed by interval debulking surgery (if optimal debulking was not achieved with primary surgery), and then paclitaxel 135 mg/m(2) over 24 hours on day 1 and cisplatin 75 mg/m(2) on day 2 at 21-day intervals for four cycles. RESULTS: Such sequential couplets are feasible. Myelotoxicity was the major toxic effect, but it was of short duration. The granulocyte nadir with topotecan/cisplatin occurred late (median, day 18), so retreatment on day 21 was not always possible. There was no unexpected nonhematologic toxicity. The regimen was active in this group of patients who had undergone largely suboptimal debulking surgery. In 34 patients with clinically measurable disease, the overall response rate was 78%, and 30 (77%) of the 39 patients with elevated CA 125 levels at baseline had normalization of CA 125 levels by the end of therapy. CONCLUSION: Sequential couplets of cisplatin/topotecan followed by paclitaxel/cisplatin are feasible. The efficacy data in this suboptimal group of patients has encouraged us to proceed with a randomized study based on this approach.

Homologs of idoxifene: variation of estrogen receptor binding and calmodulin antagonism with chain length.

A series of homologs of idoxifene [1a, (E)-1-[4-(N-pyrrolidinoethoxy)phenyl]-1-(4-iodophenyl)-2-phenyl-1-butene ] and selected homologs of 4-iodotamoxifen [2a,(E)-1-[4-(N-dimethylamino)-ethoxy]phenyl]-1-(4-iodophenyl)-2-phenyl -1-butene] with the side chain (CH(2))(n) varying in length from n=3 (1b,2b) to n=10(1i,2i) have been synthesized and tested for antagonism of of the calmodulin-dependent activity of cAMP phosphodiesterase and for binding affinity to rat uterine estrogen receptor. Compared with 1a (IC(50) =1.5 microM), the homologs showed a progressive increase in calmodulin antagonism with a maximum inhibition at n=7-9 (1f-h)(IC(50)=0.2 microM), declining at n=10 (1i) to IC(50) =1.6 microM. In the pyrrolidino series, estrogen receptor binding affinity peaked at n=3 (1b, RBA= 23; estradiol = 100), declining by n=10 (1i) to RBA = 0.4, but the homolog n=8 (1g, RBA = 3.5) was still comparable to tamoxifen (RBA = 3.9). A similar pattern of activity was seen for the dimethylamino counterparts. These compounds represent a new class of antiestrogens with potent calmodulin antagonism.

Oestrogen formation in breast: clinical and biological importance.

It has been known for many years that many breast carcinomas can synthesize oestrogens from androgens via the action of the enzyme aromatase. There has been widespread speculation on the possibility that this acts as an important intracrine source of growth stimulation. For example, there are data which indicate that clinical response to aromatase inhibitors is far more common in tumours which possess measurable amounts of aromatase. In addition, aromatase activity in the quadrant of the normal breast surrounding breast carcinomas is generally higher than in the other quadrants. However, these data are only suggestive and the case for a significant role for intratumoural aromatase in breast cancer growth remains unproven. We have recently explored this possibility by the transfection of human breast cancer cells with aromatase. By a series of experiments in athymic mice we have demonstrated that growth is supported by this intracrine source in the absence of endocrine oestrogen stimulation.

Antagonism of estrogen receptor and calmodulin association by antiestrogens is not dependent on an interaction with calmodulin.

Previously, two antiestrogens estradiol derivatives (3 and 4) bearing the basic side chain of tamoxifen were shown to impede the binding of the estrogen receptor (ER) to calmodulin (CaM)-Sepharose. In this study, the interaction of these and related compounds with calmodulin was examined using the cyclic AMP phosphodiesterase (cAMP-PDE) assay. Neither of the steroids gave any significant inhibition of the calmodulin dependent cAMP-PDE activity up to a final concentration of 20 microM. For comparison, tamoxifen and nafoxidine produced IC50 values of 6.7 microM +/- 1.0 and 7.4 microM +/- 1.1, respectively. In addition, a comparison was made of the activity of some triphenylethylene derivatives against CaM dependent cAMP-PDE and the ER-CaM Sepharose assays, but no relationship was observed. Overall, these results demonstrate that inhibition of the ER-CaM association by various steroidal and triphenylethylene antiestrogens does not relate to antagonism of calmodulin function or their binding affinity for the estrogen receptor.

Evidence that tamoxifen binds to calmodulin in a conformation different to that when binding to estrogen receptors, through structure-activity study on ring-fused analogues.

A ring-fused analogue of tamoxifen, which had previously been shown to have practically identical estrogen receptor (ER) affinity and antitumour potency against estrogen responsive cells as tamoxifen, failed to inhibit calmodulin-dependent cyclic AMP phosphodiesterase. The substitution of an extra methyl group into the ring-fused analogue, at a position which the ethyl group of tamoxifen can occupy in one of its conformations, restored the calmodulin inhibition. Also, the replacement of the tamoxifen ethyl group by methyl diminishes calmodulin inhibition. Direct interaction of these tamoxifen analogues with calmodulin was demonstrated through the use of the fluorescent probe, 2-p-toluidinyl-naphthalene-6-sulfonic acid (TNS). These findings lead to the conclusion that tamoxifen binds to calmodulin in a conformation not accessible to the fused analogue and therefore likely to be different to that which binds to the ER. Also, the results on the ring-fused analogues indicate that the calmodulin binding cannot be essential for antitumour activity.

Inhibition of protein prenylation by metabolites of limonene.

The monoterpenes limonene and perillyl alcohol are undergoing clinical evaluation in cancer patients. In this paper, we report the chemical synthesis, characterisation, and quantitation in patients' plasma of a novel human metabolite of limonene, which is identified as an isomer of perillic acid. The synthesis of R-perillic acid is also described, because previous reports on the activity of perillic acid against isoprenylation enzymes refer to the S-enantiomer, although it is the R-enantiomer which is the metabolite of R-limonene. The above monoterpenes, with several related compounds, were assayed for inhibitory activity towards the isoprenylation enzymes in rat brain cytosol. Although R- and S-limonene are only weak inhibitors of the isoprenylation enzymes, their major metabolites, perillic acid and perillyl alcohol, are more potent inhibitors, with IC50 values in the low mM range. The metabolites possess greater activity towards the geranylgeranyltransferase type I enzyme than farnesyltransferase, while the novel metabolite displays IC50 values similar to those of perillic acid suggesting that it may contribute to the in vivo activity of limonene.

The control and biological importance of intratumoural aromatase in breast cancer.

The existence of aromatase activity in human breast carcinomas has been established for about 20 years but the clinical and biological importance of this remains unclear. A number of studies in clinical material suggest that aromatase activity may be a prerequisite of response to aromatase inhibitors and that aromatase activity may be enhanced in those tumours relapsing during treatment with one such inhibitor, aminoglutethimide. These results would carry more significance, however, if it was demonstrable that the growth of breast carcinomas is affected by the conversion of androgens to oestrogens by intratumoural aromatase. We have tried to address this by establishing model systems with aromatase-transfected MCF7 breast cancer cells. We have demonstrated that these cells can be stimulated mitogenically with androgen and that this proliferation is suppressible with aromatase inhibitors. Similarly the growth of aromatase transfected cells but not wild type cells as xenografts is supported by androstenedione and inhibitable by both the steroidal aromatase inhibitor, 4-hydroxyandrostenedione and non-steroidal inhibitor, CGS 20267. Work with the former of these, which is a suicide inhibitor allowed us to demonstrate that growth can proceed with aromatase activity approximating to the highest level seen in breast carcinomas indicating that at least at this extreme level the intratumoural conversion of androgens to oestrogens may indeed be able to support tumour growth. Further work with this mode system should allow us to define the minimal amount of intratumoural activity which can support tumour growth.