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e21529 Background: The US Food and Drug Administration (FDA) advisory panel has discouraged the use of laparoscopic power morcellators (LPM) for removal of uterus or uterine fibroids in April 2014....

We investigated the effect of antagonists of growth hormone-releasing hormone (GHRH) MZ-J-7-138 and JV-1-92 on H460 human non-small cell lung carcinoma (NSCLC) xenografted orthotopically into nude mice. Treatment with MZ-J-7-138 or JV-1-92 inhibited orthotopic growth of H460 NSCLC by 52–65% ( P < 0.001) and was associated with a significant decrease in protein expression of K-Ras, cyclooxygenase-2 (Cox-2) and phospho-Akt (pAkt). In other experiments, treatment with MZ-J-7-138 or docetaxel reduced tumor volume of s.c. xenografted H460 human NSCLC by 30–36% ( P < 0.01). The combination of MZ-J-7-138 and docetaxel resulted in a synergistic growth inhibition of H460 NSCLC xenografts of 63%. MZ-J-7-138 alone or in combination with docetaxel significantly reduced protein levels of K-Ras, Cox-2, and pAkt by 56–63%. Docetaxel given singly diminished the protein levels only of Cox-2 and did not affect K-Ras and pAkt. High-affinity binding sites, mRNA, and protein expression of pituitary GHRH receptors and its splice variant (SV) 1 were found in H460. H460 NSCLC cells contained GHRH peptide, and its growth was significantly inhibited in vitro by 10 μM MZ-J-7-138 ( P < 0.001). Serum insulin-like growth factor 1 (IGF1) was not reduced by either GHRH antagonists. These findings suggest that antiproliferative effects of GHRH antagonists in H460 NSCLC are associated with down-regulation of K-Ras, Cox-2, and pAkt. In conclusion, GHRH antagonists in combination with docetaxel synergistically inhibit growth of H460 NSCLC and the expression of K-ras, Cox-2, and pAkt, which might abrogate the signal transduction pathways for cell growth stimulation and therapeutic resistance.

The aim of this study was to investigate the effect of treatment of experimental ovarian cancers with targeted cytotoxic analogs as single compounds and in combination. Targeted cytotoxic analogs of bombesin (AN-215), somatostatin (AN-238), and luteinizing hormone-releasing hormone (AN-207) consisted of 2-pyrrolinodoxorubicin (AN-201) linked to the respective peptide carrier. AN-238 at 200 nmol/kg significantly inhibited growth of UCI-107, ES-2 and OV-1063 ovarian cancers. AN-215 alone at 200 nmol/kg and its combination with AN-238 at one-half of the dose were also able to inhibit the growth of UCI-107 tumors. A combination of AN-238 with AN-207at 50% of the dose strongly suppressed the proliferation of ES-2 and OV-1063 ovarian tumors. Cytotoxic radical AN-201 was toxic and had no significant effect on tumor growth. In contrast, the toxicity of the conjugated peptide analogs was low. Because ovarian cancers tend to acquire chemoresistance, we used real-time PCR to measure the mRNA expression of multidrug resistance protein 1, multidrug resistance-related protein 1, and breast cancer resistance protein after treatment. Low or no induction of multidrug resistance protein 1, multidrug resistance-related protein, and breast cancer resistance protein occurred after treatment with AN-238, AN-215, and the combination of AN-238 with AN-207 or AN-215. These results demonstrate that a therapy with cytotoxic analogs such as single agents and combinations is effective and nontoxic. Our work suggests that cytotoxic peptide analogs of luteinizing hormone-releasing hormone, somatostatin, and bombesin could be used for the therapy of ovarian cancers, considering the lack of induction of chemoresistance.

An improved process for the enantioselective hydrolysis of prochiral 2-aryl-2-alkyl-disubstituted diethyl malonates catalyzed by pig liver esterase (PLE) was developed. With diethyl 2-phenyl-2-methylmalonate as a model substrate, the highest enantioselectivities (96% ee; /?-isomer) were achieved when carrying out the process in the presence of a suitable mixture of cosolvents (buffer-i-PrOH-t-BuOH, 8:1:1). The process also works efficiently at higher substrate concentrations. The reaction was carried out on a multi-gram preparative scale, leading to a conversion of>95%, an enantioselectivity of 96% ee, and a yield of 83% at a substrate concentration of 200 mM.

Systemic lupus erythematosus (SLE) with or without accompanying antiphospholipid antibody syndrome (APLS) is known to cause myocardial ischemia via multiple mechanisms, including accelerated coronary atherosclerosis, impaired coronary vasomotor function, spontaneous intracoronary thrombus formation, or endothelial dysfunction in the context of cardiac syndrome X (CSX). We present the case of a young woman with SLE and APLS who presented with myocardial ischemia and peculiar echocardiographic evidence of multiple small septal perforator infarcts despite a normal coronary angiogram, a rare combination.

The first aminoacylase-catalyzed enantioselective synthesis of aromatic beta-amino acids is reported. The presence of an N-chloroacetyl group as acyl group in the substrate as well as the use of porcine kidney acylase I as a suitable enzyme component are prerequisites for this resolution process whereby optically active beta-amino acids are formed with high enantioselectivities of >98% ee.

The enantioselective enzymatic deamidation of ( rac )- N -carbamoyl amino acid amides (Cbm-AA-NH 2 ) to enantiopure ( L )- N -carbamoyl amino acids (Cbm-AA-OH) is described for the first time. Via fast screening methods of biocatalysts several proteases like Chirazyme P1, Chirazyme P2 and Subtilisin were identified, which give conversions of up to 47% and >98% ee. This conversion is most productive on aliphatic and primary amino acids.

Purpose: Over 50% of heart failure (HF) patients delay seeking help for worsening symptoms until these reach acute levels and require emergency hospitalisation. This metasynthesis aimed to identify andexplore factors influencing timely care-seeking in patients with HF. Methods: Electronic databases searched were Medline, EMBASE and CINAHL. Studies were included if they were peer reviewed journal articles written in English, and reported perspectives of HF patients following qualitative data collection and analysis. Forty articles underwent analysis following the approach of Thomas andHarden. Leventhal’s self-regulatory model (SRM) was used to organise the literature. Results: Much of the literature fit within the SRM, however this model did not account for all factors that influence patients’ care-seeking for worsening symptoms. Factors not accounted for included patients’ appraisals of previous careseeking experiences, perceived system and provider barriers to accessing care, and the influence of external appraisals. When added to factors already represented in themodel, such asmisattribution of symptoms, not identifyingwithHF diagnosis, cognitive status, lack of understanding information provided, adaptation to symptoms, and emotional responses, a more comprehensive account of patients’ decision-making was revealed. Implications: This metasynthesis identified factors, as yet unaccounted for, in a prominent model, and has suggested a more comprehensive framework for addressing care-seeking in HF patients. This information can be used to tailor education, communication, and service initiatives to improve HF patients’ responses to worsening symptoms.

Background: Recent literature suggests that the valvular phenotype in bicuspid aortic valve (BAV) may result in different degrees of valve dysfunction and aortopathy due to abnormal helical aortic flow. Methods: We reviewed 4500 echocardiogram reports and selected 46 patients (76%male, age 48 +/16 years) with definite BAV, anddefined 3phenotypesright and left cusp fusion (type 1; n = 30), and non-coronary cusp with either right (type 2; n = 10) or left cusp fusion (type 3; n = 6). We used a previously published calcium scoring system and current guidelines for chamber quantification, valvular disease and aortic dimensions. Results: The sinus of Valsalva was significantly larger in type 1 vs. type 2 (4.0 +/0.6 vs. 3.5 +/0.6 cm; p=0.03), however, when indexed to body surface area (BSA), this statistical difference was lost (2.0 +/0.4 vs 1.8 +/0.4 cm/m2; p = 0.12). Additionally, there was no difference between groups for indexed sino-tubular junction, proximal ascending aorta and transverse arch. Type 3 BAV had a significantly higher calcium score (2.7 vs. 0.8 [type 2] vs. 0.9 [type 1]; p=0.02) as well as higher average corrected transvalvular maximum pressure gradients (45 +/23 vs. 29 +/40 vs. 19 +/18mmHg; p= 0.0056 for comparison type 3 vs. type 1). Conclusions: In our patient cohort no BSA-indexed difference in the degree of aortopathy was found. The (rare) presence of fusion of the left and non-coronary cusp may be predictive of a more ‘malignant’ BAV phenotype.

To the Editor: A 61-year-old postmenopausal woman has presented 3 times within 4 years with acute tako-tsubo cardiomyopathy (TTC). Each admission was precipitated by a heated argument and characterized by severe central chest pain, anterior ST-segment elevation, and elevated serum troponin levels; however, angiography revealed normal coronary arteries. Inotropic and noninvasive ventilatory support was required on all 3 occasions and intubation on 1 occasion. Left ventricular (LV) apical thrombus complicated the first episode but resolved with anticoagulation. Rapid normalization of LV systolic function on echocardiography, as well as resolution of the ST-segment elevation on electrocardiography, was observed after each presentation. During the patient's latest admission, coronary angiography (on day 10) revealed a large and mobile LV apical thrombus (Figure 1, top). This thrombus had not been observed on transthoracic echocardiography performed 6 days before angiography, and it had developed despite administration of aspirin and subcutaneous heparin and in the absence of atrial fibrillation on continuous monitoring. FIGURE 1. Top, Left ventricular apical thrombus (circle) as seen by ventriculography (day 10 of most recent admission). Bottom, Left ventricular apical thrombus (circle) and left atrial appendage thrombus (arrow) as seen on cardiac magnetic resonance imaging (day ... Cardiac magnetic resonance imaging was performed to exclude alternative myocardial pathology. A scan obtained on day 12 showed normalization of LV systolic function with no late gadolinium enhancement. However, in addition to the apical thrombus in the LV, the scan revealed a large thrombus in the left atrial appendage (LAA) (Figure 1, bottom, supplemental video). Echocardiographic assessment of left atrial (LA) function at presentation was suggestive of transient LA enlargement and dysfunction (Table). Screening for thrombophilia was negative. TABLE. Echocardiographic Left Atrial Parameters During the Acute and Recovery Phase of Tako-Tsubo Cardiomyopathy Left ventricular apical thrombus formation is a known complication of TTC and has been reported in up to 8% of case series,1 with potential for embolic sequelae. To our knowledge, this is the first published report of LAA thrombus complicating TTC independent of atrial fibrillation. We hypothesize that the following mechanisms are important contributors to thrombus formation in the setting of acute TTC: Catecholamine excess–induced platelet activation and aggregation. Plasma catecholamine levels have been found to be higher at presentation in patients with TTC than in those with ST-segment elevation myocardial infarction.2 Both norepinephrine and epinephrine have been shown to induce platelet activation.3 Catecholamine-mediated endothelial and cardiomyocyte injury. Surges of catecholamines may induce cardiac myocyte injury via cyclic adenosine monophosphate–mediated calcium overload4 or indirectly due to catecholamine-induced endothelial dysfunction and associated damage to underlying myocytes.5 Myocytes in the LV apex are thought to be particularly sensitive to excessive levels of catecholamines, partly as a result of the higher endothelial to myocardial ratio.6 Our finding of an LAA thrombus suggests that myocytes in the left atrium may also be sensitive to the pathological milieu of TTC. Atrial dysfunction may be compounded by increased atrial filling pressures secondary to increases in LV end-diastolic pressure. Consistent with this and the current case, patients with TTC have been shown to have worse LA function compared with those with ST-segment elevation myocardial infarction.7 Although the occurrence of the LV apical thrombus in the episode of TTC we describe was most likely caused by acute ventricular wall akinesis, we suggest that increased platelet activation and aggregability due to catecholamine release in conjunction with LA stretch and subsequent endothelial injury may also act as contributory factors that favor thrombus development. The global nature of these factors may explain thrombosis in other cardiac chambers, such as the LAA as described in our case. Given the prothrombotic state that characterizes TTC episodes, a review of anticoagulation protocols for this condition may be warranted.

Epitaxial Ag(111) films have been grown on mica. They exhibit flat terraces of a few 100 nm diameter, suitable for nanoscale modification with the scanning tunneling microscope (STM). Under ambient conditions, surface modifications of a few nanometers diameter were produced by raising the bias from below 1 V to a bias between 3 and 7 V for less than 50 ns. The steady‐state current could be limited to 2 pA. This means that the modification is initiated while only a few electrons pass the tunneling junction, indicating that it is not a current effect. At positive sample bias, usually holes are formed, while at negative bias hillocks occur. In the case of hole formation, the current does not change significantly on a time scale of 10 μs. When hillocks are formed, the current may rise after the application of the voltage pulse. It was limited to 4 nA by the external circuitry and remains saturated until the tip is withdrawn on a time scale of milliseconds, i.e., the characteristic for the feedback loop contro...

TPS11124 Background: Triple-negative breast cancer (TNBC) is a subtype of breast cancer that is clinically negative for expression of estrogen and progesterone receptors (ER/PR) and human epidermal growth factor receptor-2 (HER2). It is characterized by its unique molecular profile, aggressive behavior, distinct patterns of metastasis, and lack of commercially available targeted therapies. Chemotherapy has been the mainstay of treatment for women with TNBC, but this current standard-of-care is suboptimal. AEZS-108 is an LHRH-cytotoxic hybrid drug whose rational design covalently couples the carrier D-Lys6-LHRH (an LHRH agonist) to the cytotoxic doxorubicin radical. Because LHRH receptors are expressed in a majority of TNBC, AEZS-108 represents a novel way to selectively deliver cytotoxic chemotherapy in patients with TNBC via a new therapeutic target. Methods: In this open label randomized two-arm multicenter phase II study, patients will be randomized in a 1:1 ratio into one of the two treatment arms: AEZS-108 (267 mg/m2 every 21 calendar days) [Arm A] or SSC (standard single agent cytotoxic chemotherapy [Arm B]) at discretion of treating oncologist cycled every 21 calendar days. Stratified randomization will be used with number of prior lines of therapies (1-2 vs. >2), ECOG performance status 0-1 vs. 2, and liver metastases (absent vs. present). Analysis of the main study endpoint, TTP, will follow a group sequential design with two interim analyses, including the final analysis. O’Brien Fleming stopping boundaries will be used. The primary endpoint is to evaluate the median time to progression (TTP) of AEZS-108 in patients with chemotherapy resistant advanced TNBC treated with AEZS-108 in relation to patients receiving standard single agent cytotoxic chemotherapy. Secondary endpoints include: overall response, clinical benefit, duration of response, overall survival, toxicity profile and quality of life (QoL). Clinical trial information: NCT01698281.

GHRH antagonists have been shown to inhibit growth of various human cancer cell lines xenogratted into nude mice including estrogen receptor negative human breast cancers. Previous observations also suggest that GHRH locally produced in diverse neoplasms including breast cancer might directly affect proliferation of tumor cells. In the present study we demonstrate that a novel highly potent GHRH antagonist JMR-132 strongly inhibits the proliferation of both estrogen receptor negative SKBR 3 and estrogen receptor positive ZR 75 human breast cancer cell lines in vitro. The proliferation in vitro of ZR 75 and SKBR 3 was increased after direct stimulation with GHRH(1-29)NH 2 . The GHRH antagonist JMR-132 had a significant antiproliferative activity in the absence of GHRH and nullified the proliferative effect of GHRH in these cell lines. SKBR 3 and ZR 75 expressed the GHRH ligand as well as the pituitary type of GHRH-receptor, which likely appears to mediate the antiproliferative mechanisms in these cell lines. These in vitro results suggest that JMR-132 is a potent inhibitor of breast cancer growth, independent of the estrogen receptor status. Further investigations on the combination treatment with endocrine agents affecting the estrogen pathway and GRHR antagonists are needed in order to improve the treatment of breast cancer.

Background: Cardiovascular prevention demonstrates significant gaps between guidelines and clinical practice. Recent European data suggests increasing rates of obesity, diabetes and smoking in patients with coronary heart disease (CHD). We assessed the prevalence of traditional risk factors and guideline compliance in Australians with CHD and compared these to a large European cohort. PCI outcomes were stratified by compliance with lipid guidelines. Methods: We prospectively collected baseline data on 2158 patients undergoing percutaneous intervention (PCI) at six Australian private hospitals between October 2008 and January 2011. These data were compared to Euroaspire III, a survey of 2392 patients with CHD from 2006 to 2007.

Annual dobutamine stress echocardiography (DSE) is used to detect cardiac allograft vasculopathy in heart transplant (HTX) recipients. Atropine is commonly used in non-transplant patients to increase the sensitivity of DSE by achieving the target heart rate (THR=85% of 220 – patient’s age). Orthotopic HTX completely denervates the donor’s heart, with little evidence to suggest parasympathetic reinnervation. As such, the efficacy of atropine as a chronotropic agent in HTX patients undergoing DSE is unknown. A retrospective review from August 2008 to February 2011 yielded 173 consecutive, individual HTX patients (56.5± 13 years; time since HTX 9.5± 5 years) after excluding seven patients on negatively chronotropic medication within 48 hours prior to DSE. Standard protocol dobutamine was commenced at 5mcg/kg/min. If THR was not attained at 50mcg/kg/min, a bolus of maximal 1200mcg atropine was given. 123 p p 6 i v y y p

e13627 Background: Antagonists of growth hormone releasing hormone (GHRH) are being developed fort he treatment of various cancers. In this study we investigated the effectiveness of treatment with...

A 69-year-old previously healthy woman presented in extremis with multiorgan failure after 7 days of diarrhoea, abdominal discomfort, fatigue, and increasing pain and discoloration of her distal limbs. Initial assessment demonstrated a drowsy, obese woman with marked distal acrocyanosis and early gangrene ( Panels A–C ). Doppler ultrasound of her limbs showed absent flow signal in the distal left ulnar artery and in both the left distal posterior and anterior tibial arteries but normal flow elsewhere. There was …

A previously well 26-year-old man presented with severe retrosternal chest pain. There were no associated symptoms, and no relationship of the pain to inspiration, exertion, or posture. He was a frequent user of cocaine, most recently 48 h prior to presentation. Initial cardiac enzymes were substantially elevated [creatine kinase level 710 U/L (normal range 40–300 U/L) and troponin I 10.3 µg/L (normal value

reduce door to balloon (DTB) time in STEMI. Shorter DTB times are associated with reduced mortality. The main barrier to implementing ED CCL activation is concern of inappropriate activation of the CCL. Aim:Tocompare falsepositive ratesof suspectedSTEMI patients undergoing emergency coronary angiography by cardiology verses senior ED activation of the CCL. Methods: All patients undergoing emergency cardiac catheterisation forSTEMI from2007 to2009wereanalysed. Falsepositive rateswere comparedbefore andafter implementing a protocol enabling independent ED activation of the CCL (2007–2008 vs. 2009). Some patient characteristics required ED to communicate with cardiology prior to CCL activation (elderly, borderline ECG changes, out of hospital arrest, LBBB, significant co-morbidities). Patient files, ECGs, coronary angiograms and left ventriculograms were reviewed in all patients undergoing emergency angiography without percutaneous coronary intervention to determine diagnosis, management and cause of the false positive cases. Results: Cardiology 2008–2009 (n= 150) ED 2009 (n= 84) Primary PCI 118 (79%) 70(83%) Medical management 11 (7%) 4 (5%) Surgery 3 (2%) 1 (1) False positive 18 (12%) 9 (11%) (NS) Causes of false positives: Chest pain of unclear cause with either early repolarisation of ST segments or LBBB (63%, 7/27). Takotsubo cardiomyopathy (22%, 6/27), myo/pericarditis (11%, 3/27) and pulmonary embolism (5%, 1/27). Conclusion: False positive rates in patients undergoing emergency angiography for suspected STEMI is not increasedwithacontrolledsystemofemergencyphysician activation of the cardiac catheterisation laboratory. doi:10.1016/j.hlc.2010.06.975

Introduction: Launceston General Hospital (LGH) is a regional/rural centre for primary PCI and does not have onsite cardiac surgery. In order to assess the quality of care, in the management of acute ST elevationmyocardial infarction (STEMI) patients, undergoing primary PCI, an audit was performed at the LGH. Methods:A reviewwas undertaken of all patients taken to the cardiac catheterization lab for primary PCI between January 2007 and December 2009. Patients transferred to LGH following thrombolysis from an outside hospital were excluded. Thrombolysiswithin the LGHwasnot performed and thus this represents a consecutive cohort of STEMI patients. Results: 272 patientswith acute STEMIhadprimary PCI performed. Culprit vessels were the right coronary artery in 40%, left anterior descending 34%, circumflex in 12% and branch disease in the remaining. Fifty two percent of the patients had multivessel disease and 2 patients had previous coronary arterybypass graft (CABG). Tenpercent of patients had ejection fraction

Introduction:Triple-negative breast cancers are characterized by aggressive growth and early metastasic spread. Some preliminary clinical data have demonstrated good anti-tumor activity of platinum derivatives. 3rd generation compound Lobaplatin* has shown a favorable toxicity profile as compared to Cisplatin. We therefore evaluated this compound in in vitro models of triple negative breast cancers.Study design:Triple-negative humane breast cancer cell lines HCC 1937 and HCC 1806 were treated with increasing concentrations of Lobaplatin and Cisplatin (0,16-10 μm). Cells were incubated for 24, 48 and 72 h with both substances in serum-free and serum-containing medium, in order to evaluate cytotoxic effects in proliferating as well as in metabolically inactive cells. Induction of apoptosis was tested by cleavage of PARP and Caspase 3 as demonstrated by western blot analysis. Subsequently cells were coincubated with Lobaplatin and multi-caspase inhibitor ZVAD-fmk, in order to check if cell death induced by Lobaplatin can be abrogated by inhibition of classical apoptosis. Cytotoxic effects were evaluated by crystal-violet assay. To investigate in which phase of the cell cycle cytotoxicity is most pronounced, cell cycle FACS analysis was performed after treatment with various concentrations of Lobaplatin.Results:Lobaplatin showed a somewhat better anti-tumor activity in both cell lines than Cisplatin. Lobaplatin Induced cleavage of PARP and procaspase 3 indicative for induction of classical apoptosis. However, cytotoxic effects of Lobaplatin were not decreased by multi-caspase inhibitor ZVAD-fmk. Cell-cycle FACS analysis showed, that sub-G0/1 fraction (indicactive for apoptotic/necrotic cells) was increased and G2 fraction was decreased dose-dependently by treatment with Lobaplatin.Conclusion:Lobaplatin showed a good anti-tumor activity in in vitro models of triple negative breast cancers which was at least equal to Cisplatin. Main mechanism of ytotoxicity was programmed cell death, which could not be abrogated by multi-caspase inhibition. Due to the good anti-tumor activity and the favorable toxicity profile, Lobaplatin should be considered for clinical studies in triple negative breast cancers.*Aeterna/Zentaris GmbH, Frankfurt/M Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 6115.

619 Background: Triple negative breast cancers (TNBC) represent a distinct subtype of breast cancer being negative to ER, PR and HER2 and are associated with poor prognosis. Limited systemic treatment options exist for TNBC. TNBC cells express somatostatin receptors (SSTR). Therefore, to investigate preclinical characteristics of TNBC we used a novel targeted cytotoxic somatostatin analogue AN-162 containing doxorubicin (DOX) which binds to the subtypes 2, 3 and 5 of SSTR. Methods: The expression of SSTR in HCC 1806 human TNBC cell line was detected by RT-PCR. Cytotoxic effect of AN-162 in vitro was visualized by ethidium bromide staining fluorescence microscopy. Internalization of AN-162 into HCC 1806 cells was tested by 125Iodide-labeled AN-162 uptake assays and the presence of DOX in the nucleus was measured by fluorescence assays after separating the nucleus from the cytoplasm. For in vivo experiments, HCC 1806 TNBC cells were xenografted subcutaneously into nude mice which were then randomized into four groups receiving AN-162, DOX, an unconjugated mixture of DOX and somatostatin analogue RC-160 at the same equimolar dose of 2.5 μmol/kg (1.45 mg/kg Dox equivalent) i.v. (q7d 4x) and vehicle solution control. Results: HCC 1806 TNBC cell line was positive for the expression of all five SSTR receptor subtypes. Ethidum bromide staining of cells treated with 2.5 μM of AN-162 for 30 min demonstrated cell death after 24h by fluorescence microscopy. Uptake assays with AN-162 showed specific internalization of AN-162 into the cells mediated through the sstrs. After treatment of the cells with 2.5 μM AN-162 for 10 or 30 min, DOX could be detected in the nucleus by fluorescence assays. In vivo, AN-162 significantly (p No significant financial relationships to disclose.

Abstract #2137 Introduction Agonists of LHRH are a treatment option in premenopausal women with estrogen receptor positive breast cancer. The treatment with those agonists decreases the levels of FSH and LH in the blood and thus reduces the levels of sex hormones. Patients with estrogen receptor negative breast cancers do not benefit from therapy with LHRH agonists. Antagonists of LHRH lower LH, FSH and sex steroid levels but without the initial flare up of FSH and LH. In addition to the endocrine effects, Cetrorelix also shows a direct inhibition of cell growth in LHRH receptor (LHRH-R) positive gynecological cancer in vitro where alterations of FSH, LH and sex hormone levels are clearly excluded. In view of these findings we decided to investigate Cetrorelix on the tumor growth in two estrogen receptor negative but LHRH-R positive breast cancer cell lines. Materials and Methods The mRNA expression of LHRH-R was detected by PCR. For proliferation assays cells were treated with increasing doses of Cetrorelix acetate in 0.5% FBS supplemented RPMI 1640 media. MTS assays were performed after 72h. Fluorescence microscopy using ethidium bromide staining was performed to show cell death. In the in vivo study, nude mice were treated with Cetrorelix pamoate preparation at a dose of 3mg s.c. releasing an estimated 100mg Cetrorelix/day. Results MX1 and MDA-MB-231 estrogen receptor negative human breast cancer cell lines were positive for the expression of mRNA for LHRH-R. The cell proliferation in vitro of MX1 and MDA-MB-231 lines treated with different concentrations of Cetrorelix was significantly inhibited in a dose dependent manner. Time and dose dependent cell death was observed by fluorescence staining. Experimental treatment in vivo with Cetrorelix pamoate preparation reduced a significant inhibition of tumor growth in MX1 xenografts as compared to the Controls after 14 days and the suppression remained significant until the end of the study on day 28. MDA-MB-231 xenografts treated with Cetrorelix also showed a significant inhibition of tumor growth compared to the Control as early as day 7 and the inhibition remained significant until the end of the study on day 28. Conclusion Our results indicate a direct inhibitory effect of Cetrorelix on LHRH-R positive breast cancers. Since LHRH-R are expressed in ER negative breast cancers, these findings suggest a new approach to the treatment of LHRH-R positive breast cancer patients independent of the estrogen receptor status. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 2137.

The Scanning Tunneling Microscope (STM) will be discussed as a tool to investigate the polymer—metal interface on the one hand and to address individual organic molecules on the other hand. Examples will be given for two classes of systems: (i) Single polymer molecules on a conducting substrate (alkylated cellulose on graphite) and (ii) two organic conductors (a radical cation salt and doped polyacetylene) interfaced and imaged by the tip of the STM.

Monolayers of the two homologues dihexadecylbenzene and didodecylbenzene were adsorbed at the interface between highly oriented pyrolytic graphite (HOPG) and an organic solution. The derivatization of a small molecule, in this case benzene, with long alkyl sidechains is shown to be a method to immobilize various molecular entities at the interface between HOPG and an organic solution. In situ STM studies at the internal interface revealed that the first adsorbed monolayer of the dialkyl‐substituted benzenes exhibits a lamellar phase with the molecules extended and oriented parallel to the basal plane of graphite. Bias‐dependent experiments allowed to either image preferentially the underlying substrate (at low bias) or the molecular adsorbate (at higher bias), without disrupting the adsorbate layer. From such experiments it was concluded that the alkane sidechains tend to orient parallel to a graphite lattice axis. High resolution images revealed different types of packing within a lamella, which were separated by sharp domain boundaries. Also packing defects involving individual molecules were observed. Most interesting, fast image recording on video tape allowed to directly follow the dynamics of such individual defects on the time scale between 100 ms and several minutes, i.e. the relevant timescale for the slow dynamics in crystalline organic phases.Monolayers of the two homologues dihexadecylbenzene and didodecylbenzene were adsorbed at the interface between highly oriented pyrolytic graphite (HOPG) and an organic solution. The derivatization of a small molecule, in this case benzene, with long alkyl sidechains is shown to be a method to immobilize various molecular entities at the interface between HOPG and an organic solution. In situ STM studies at the internal interface revealed that the first adsorbed monolayer of the dialkyl‐substituted benzenes exhibits a lamellar phase with the molecules extended and oriented parallel to the basal plane of graphite. Bias‐dependent experiments allowed to either image preferentially the underlying substrate (at low bias) or the molecular adsorbate (at higher bias), without disrupting the adsorbate layer. From such experiments it was concluded that the alkane sidechains tend to orient parallel to a graphite lattice axis. High resolution images revealed different types of packing within a lamella, which were sep...

Silver, gold, palladium, and chromium films have been evaporated onto mica at substrate temperatures ranging from −150 °C to +400 °C. Scanning tunneling microscopy (STM) images were obtained under ambient conditions. Silver and gold films exhibit an increasing grain size together with a grain flattening as the substrate temperature increases. At 275 and 400 °C for silver and gold, respectively, terraces with dimensions of the order of more than 100 nm are formed. However, also characteristic holes on the scale of a few 10 nm were always present. In addition, the gold films exhibit characteristic holes on the nanometer scale. While the larger holes are also visible on scanning electron microscopy micrographs, the smaller are not. Low‐energy electron diffraction patterns prove the (111) orientation of both, silver and gold films; however, the quality of the silver patterns is better, consistent with the more perfect terraces as seen by STM. Palladium, evaporated at temperatures up to 350 °C did not exhibit similarly large and flat terraces. An improvement is achieved if prior to the palladium, silver is evaporated at elevated temperatures. Chromium, contrary to the fcc metals Ag, Au, and Pd crystallizes bcc, and forms a stable surface oxide under ambient conditions. The reproducibility of its STM images under ambient conditions depends on the applied bias and can be attributed to the surface oxide. Films evaporated at 50 °C exhibit a grainy structure. For the 350 °C films areas with a columnar morphology have been observed. In conclusion, epitaxially grown Ag(111) films evaporated at 275 °C onto mica have been shown to exhibit large flat terraces suitable for nanoscale modifications and chemisorption studies with the STM.