The effect of olive leaf extract on platelet function

Background Epidemiological studies have shown a reduced incidence of cardiovascular disease in the Mediterranean population attributed to the consumption of dietary olive oil rich in antioxidants. This has lead to increased interest in the antioxidant properties of other phenolic compounds of olive tree products. It has been suggested that olive leaf extract may also have health benefits due to its antioxidant and anti-inflammatory activities. Antioxidants can prevent the effects of oxidative metabolism by scavenging free radicals and decreasing the hyperactivity of platelets associated with the development of occlusive thrombosis. No studies to date have investigated the effects of olive leaf extract on platelet function to our knowledge. Improved understanding of the antioxidant properties of olive leaf extract and its effect on platelet function could lead to improved cardiovascular health. Objective The current study used an olive leaf extract prepared from the Olea europaea L. tree. The aim was to determine if polyphenols in olive leaf extract would reduce platelet activity and, to establish an optimal dose in vitro that would reduce platelet aggregation and ATP release. Design Eleven subjects with normal platelet counts (150–400 x 109/L) were recruited for the current in vitro study. Olive leaf extract was added to citrated whole blood to obtain five concentrations ranging from 5.4 ug/mL to 54.0 ug/mL for a dose response curve. Baseline samples, without olive leaf extract were used as a negative control for each subject. After 2 hours incubation with olive leaf extract samples were analyzed for platelet aggregation and ATP release from platelets stimulated by the addition of collagen. Results Whole blood analysis (n=11) showed a clear dose-dependant reduction in platelet aggregation with the increasing olive leaf extract concentrations (p<0.0001). There was also a similar decrease in ATP release from collagen stimulated platelets (p=0.02). Conclusion In the current study the olive leaf extract obtained from Olea europaea L. inhibited platelet aggregation and ATP release from collagen stimulated platelets in vitro. This study suggests olive leaf extract may prevent occlusive thrombosis by reducing platelet hyperactivity.

First flush behaviour in urban residential catchments

The current state of knowledge in relation to first flush does not provide a clear understanding of the role of rainfall and catchment characteristics in influencing this phenomenon. This is attributed to the inconsistent findings from research studies due to the unsatisfactory selection of first flush indicators and how first flush is defined. The research study discussed in this thesis provides the outcomes of a comprehensive analysis on the influence of rainfall and catchment characteristics on first flush behaviour in residential catchments. Two sets of first flush indicators are introduced in this study. These indicators were selected such that they are representative in explaining in a systematic manner the characteristics associated with first flush. Stormwater samples and rainfall-runoff data were collected and recorded from stormwater monitoring stations established at three urban catchments at Coomera Waters, Gold Coast, Australia. In addition, historical data were also used to support the data analysis. Three water quality parameters were analysed, namely, total suspended solids (TSS), total phosphorus (TP) and total nitrogen (TN). The data analyses were primarily undertaken using multi criteria decision making methods, PROMETHEE and GAIA. Based on the data obtained, the pollutant load distribution curve (LV) was determined for the individual rainfall events and pollutant types. Accordingly, two sets of first flush indicators were derived from the curve, namely, cumulative load wash-off for every 10% of runoff volume interval (interval first flush indicators or LV) from the beginning of the event and the actual pollutant load wash-off during a 10% increment in runoff volume (section first flush indicators or P). First flush behaviour showed significant variation with pollutant types. TSS and TP showed consistent first flush behaviour. However, the dissolved fraction of TN showed significant differences to TSS and TP first flush while particulate TN showed similarities. Wash-off of TSS, TP and particulate TN during the first 10% of the runoff volume showed no influence from corresponding rainfall intensity. This was attributed to the wash-off of weakly adhered solids on the catchment surface referred to as "short term pollutants" or "weakly adhered solids" load. However, wash-off after 10% of the runoff volume showed dependency on the rainfall intensity. This is attributed to the wash-off of strongly adhered solids being exposed when the weakly adhered solids diminish. The wash-off process was also found to depend on rainfall depth at the end part of the event as the strongly adhered solids are loosened due to impact of rainfall in the earlier part of the event. Events with high intensity rainfall bursts after 70% of the runoff volume did not demonstrate first flush behaviour. This suggests that rainfall pattern plays a critical role in the occurrence of first flush. Rainfall intensity (with respect to the rest of the event) that produces 10% to 20% runoff volume play an important role in defining the magnitude of the first flush. Events can demonstrate high magnitude first flush when the rainfall intensity occurring between 10% and 20% of the runoff volume is comparatively high while low rainfall intensities during this period produces low magnitude first flush. For events with first flush, the phenomenon is clearly visible up to 40% of the runoff volume. This contradicts the common definition that first flush only exists, if for example, 80% of the pollutant mass is transported in the first 30% of runoff volume. First flush behaviour for TN is different compared to TSS and TP. Apart from rainfall characteristics, the composition and the availability of TN on the catchment also play an important role in first flush. The analysis confirmed that events with low rainfall intensity can produce high magnitude first flush for the dissolved fraction of TN, while high rainfall intensity produce low dissolved TN first flush. This is attributed to the source limiting behaviour of dissolved TN wash-off where there is high wash-off during the initial part of a rainfall event irrespective of the intensity. However, for particulate TN, the influence of rainfall intensity on first flush characteristics is similar to TSS and TP. The data analysis also confirmed that first flush can occur as high magnitude first flush, low magnitude first flush or non existence of first flush. Investigation of the influence of catchment characteristics on first flush found that the key factors that influence the phenomenon are the location of the pollutant source, spatial distribution of the pervious and impervious surfaces in the catchment, drainage network layout and slope of the catchment. This confirms that first flush phenomenon cannot be evaluated based on a single or a limited set of parameters as a number of catchment characteristics should be taken into account. Catchments where the pollutant source is located close to the outlet, a high fraction of road surfaces, short travel time to the outlet, with steep slopes can produce high wash-off load during the first 50% of the runoff volume. Rainfall characteristics have a comparatively dominant impact on the wash-off process compared to the catchment characteristics. In addition, the pollutant characteristics also should be taken into account in designing stormwater treatment systems due to different wash-off behaviour. Analysis outcomes confirmed that there is a high TSS load during the first 20% of the runoff volume followed by TN which can extend up to 30% of the runoff volume. In contrast, high TP load can exist during the initial and at the end part of a rainfall event. This is related to the composition of TP available for the wash-off.

Sex-based comparisons of myofibrillar protein synthesis after resistance exercise in the fed state

Sex-based comparisons of myofibrillar protein synthesis after resistance exercise in the fed state. J Appl Physiol 112: 1805-1813, 2012. First published March 1, 2012; doi:10.1152/japplphysiol.00170.2012.- We made sex-based comparisons of rates of myofibrillar protein synthesis (MPS) and anabolic signaling after a single bout of high-intensity resistance exercise. Eight men (20 ± 10 yr, BMI = 24.3 ± 2.4) and eight women (22 ± 1.8 yr, BMI = 23.0 ± 1.9) underwent primed constant infusions of L-[ring-13C6]phenylalanine on consecutive days with serial muscle biopsies. Biopsies were taken from the vastus lateralis at rest and 1, 3, 5, 24, 26, and 28 h after exercise. Twenty-five grams of whey protein was ingested immediately and 26 h after exercise. We also measured exercise-induced serum testosterone because it is purported to contribute to increases in myofibrillar protein synthesis (MPS) postexercise and its absence has been hypothesized to attenuate adaptative responses to resistance exercise in women. The exercise-induced area under the testosterone curve was 45-fold greater in men than women in the early (1 h) recovery period following exercise (P < 0.001). MPS was elevated similarly in men and women (2.3- and 2.7-fold, respectively) 1-5 h postexercise and after protein ingestion following 24 h recovery. Phosphorylation of mTORSer2448 was elevated to a greater extent in men than women acutely after exercise (P = 0.003), whereas increased phosphorylation of p70S6K1Thr389 was not different between sexes. Androgen receptor content was greater in men (main effect for sex, P = 0.049). Atrogin-1 mRNA abundance was decreased after 5 h recovery in both men and women (P < 0.001), and MuRF-1 expression was elevated in men after protein ingestion following 24 h recovery (P = 0.003). These results demonstrate minor sex-based differences in signaling responses and no difference in the MPS response to resistance exercise in the fed state. Interestingly, our data demonstrate that exerciseinduced increases in MPS are dissociated from postexercise testosteronemia and that stimulation of MPS occurs effectively with low systemic testosterone concentrations in women.

Rapid aminoacidemia enhances myofibrillar protein synthesis and anabolic intramuscular signaling responses after resistance exercise

Background: Ingestion of whey or casein yields divergent patterns of aminoacidemia that influence whole-body and skeletal muscle myofibrillar protein synthesis (MPS) after exercise. Direct comparisons of the effects of contrasting absorption rates exhibited by these proteins are confounded by their differing amino acid contents. Objective: Our objective was to determine the effect of divergent aminoacidemia by manipulating ingestion patterns of whey protein alone on MPS and anabolic signaling after resistance exercise. Design: In separate trials, 8 healthy men consumed whey protein either as a single bolus (BOLUS; 25-g dose) or as repeated, small, "pulsed" drinks (PULSE; ten 2.5-g drinks every 20 min) to mimic a more slowly digested protein. MPS and phosphorylation of signaling proteins involved in protein synthesis were measured at rest and after resistance exercise. Results: BOLUS increased blood essential amino acid (EAA) concentrations above those of PULSE (162% compared with 53%, P < 0.001) 60 min after exercise, whereas PULSE resulted in a smaller but sustained increase in aminoacidemia that remained elevated above BOLUS amounts later (180-220 min after exercise, P < 0.05). Despite an identical net area under the EAA curve, MPS was elevated to a greater extent after BOLUS than after PULSE early (1-3 h: 95% compared with 42%) and later (3-5 h: 193% compared with 121%) (both P < 0.05). There were greater changes in the phosphorylation of the Akt-mammalian target of rapamycin pathway after BOLUS than after PULSE. Conclusions: Rapid aminoacidemia in the postexercise period enhances MPS and anabolic signaling to a greater extent than an identical amount of protein fed in small pulses that mimic a more slowly digested protein. A pronounced peak aminoacidemia after exercise enhances protein synthesis.

HPLC method for preliminary analysis of constituents in rat blood after oral administration of the extract of Acanthopanax senticosus

An HPLC with SPE method has been developed for analysis of constituents in rat blood after oral administration of the extract of Acanthopanax senticosus (ASE). The plasma sample was prepared by SPE method equipped with Oasis HLB cartridge (3cc, 60 mg). The analysis was performed on a Dikma Diamonsil RP(18) column (4.6 mmx150 mm, 5 microm) with the gradient elution of solvent A (ACN) and solvent B (0.1% aqueous phosphoric acid, v/v) and the detection wavelength was set at 270 nm. The calibration curve was linear over the range of 0.156-15.625 microg/mL. The LOD was 60 ng/mL. The intraday precision was less than 5.80%, and the interday precision was less than 6.0%. The recovery was (87.30 +/- 1.73)%. As a result, 19 constituents were detected in rat plasma after oral administration of the ASE, including 11 original compounds in ASE and eight metabolites, and three of the metabolites originated from syringin in ASE. Six constituents were identified by comparing with the corresponding reference compounds.

Effect of the mediator in feedback mode-based SECM interrogation of indium tin-oxide and boron-doped diamond electrodes

Indium tin-oxide (ITO) and polycrystalline boron-doped diamond (BDD) have been examined in detail using the scanning electrochemical microscopy technique in feedback mode. For the interrogation of electrodes made from these materials, the choice of mediator has been varied. Using Ru(CN) 4− 6 (aq), ferrocene methanol (FcMeOH), Fe(CN) 3− 6 (aq) and Ru(NH 3) 3+ 6 (aq), approach curve experiments have been performed, and for purposes of comparison, calculations of the apparent heterogeneous electron transfer rates (k app) have been made using these data. In general, it would appear that values of k app are affected mainly by the position of the mediator reversible potential relative to the relevant semiconductor band edge (associated with majority carriers). For both the ITO (n type) and BDD (p type) electrodes, charge transfer is impeded and values are very low when using FcMeOH and Fe(CN) 3− 6 (aq) as mediators, and the use of Ru(NH 3) 3+ 6(aq) results in the largest value of k app. With ITO, the surface is chemically homogeneous and no variation is observed for any given mediator. Data is also presented where the potential of the ITO electrode is fixed using a ratio of the mediators Fe(CN) 3− 6(aq) and Fe(CN) 4− 6(aq). In stark contrast, the BDD electrode is quite the opposite and a range of k app values are observed for all mediators depending on the position on the surface. Both electrode surfaces are very flat and very smooth, and hence, for BDD, variations in feedback current imply a variation in the electrochemical activity. A comparison of the feedback current where the substrate is biased and unbiased shows a surprising degree of proportionality.

Validity and reliability of 3-minute nutrition screening (3-MinNS)performed by nurses on oncology and surgical patients

Background Nutrition screening is usually administered by nurses. However, most studies on nutrition screening tools have not used nurses to validate the tools. The 3-Minute Nutrition Screening (3-MinNS) assesses weight loss, dietary intake and muscle wastage, with the composite score of each used to determine risk of malnutrition. The aim of the study was to determine the validity and reliability of 3-MinNS administered by nurses, who are the intended assessors. Methods In this cross sectional study, three ward-based nurses screened 121 patients aged 21 years and over using 3-MinNS in three wards within 24 hours of admission. A dietitian then assessed the patients’ nutritional status using Subjective Global Assessment within 48 hours of admission, whilst blinded to the results of the screening. To assess the reliability of 3-MinNS, 37 patients screened by the first nurse were re-screened by a second nurse within 24 hours, who was blinded to the results of the first nurse. The sensitivity, specificity and best cutoff score for 3-MinNS were determined using the Receiver Operator Characteristics Curve. Results The best cutoff score to identify all patients at risk of malnutrition using 3-MinNS was three, with sensitivity of 89% and specificity of 88%. This cutoff point also identified all (100%) severely malnourished patients. There was strong correlation between 3-MinNS and SGA (r=0.78, p<0.001). The agreement between two nurses conducting the 3-MinNS tool was 78.3%. Conclusion 3-Minute Nutrition Screening is a valid and reliable tool for nurses to identify patients at risk of malnutrition.

Application of texture analysis in tear film surface assessment based on videokeratoscopy

Purpose Videokeratoscopy images can be used for the non-invasive assessment of the tear film. In this work the applicability of an image processing technique, textural-analysis, for the assessment of the tear film in Placido disc images has been investigated. Methods In the presence of tear film thinning/break-up, the reflected pattern from the videokeratoscope is disturbed in the region of tear film disruption. Thus, the Placido pattern carries information about the stability of the underlying tear film. By characterizing the pattern regularity, the tear film quality can be inferred. In this paper, a textural features approach is used to process the Placido images. This method provides a set of texture features from which an estimate of the tear film quality can be obtained. The method is tested for the detection of dry eye in a retrospective dataset from 34 subjects (22-normal and 12-dry eye), with measurements taken under suppressed blinking conditions. Results To assess the capability of each texture-feature to discriminate dry eye from normal subjects, the receiver operating curve (ROC) was calculated and the area under the curve (AUC), specificity and sensitivity extracted. For the different features examined, the AUC value ranged from 0.77 to 0.82, while the sensitivity typically showed values above 0.9 and the specificity showed values around 0.6. Overall, the estimated ROCs indicate that the proposed technique provides good discrimination performance. Conclusions Texture analysis of videokeratoscopy images is applicable to study tear film anomalies in dry eye subjects. The proposed technique appears to have demonstrated its clinical relevance and utility.

Bioequivalence of two tablet formulations of capecitabine and exploration of age, gender, body surface area, and creatinine clearance as factors influencing systemic exposure in cancer patients

Purpose: The objective of the study was to assess the bioequivalence of two tablet formulations of capecitabine and to explore the effect of age, gender, body surface area and creatinine clearance on the systemic exposure to capecitabine and its metabolites. Methods: The study was designed as an open, randomized two-way crossover trial. A single oral dose of 2000 mg capecitabine was administered on two separate days to 25 patients with solid tumors. On one day, the patients received four 500-mg tablets of formulation B (test formulation) and on the other day, four 500-mg tablets of formulation A (reference formulation). The washout period between the two administrations was between 2 and 8 days. After each administration, serial blood and urine samples were collected for up to 12 and 24 h, respectively. Unchanged capecitabine and its metabolites were determined in plasma using LC/MS-MS and in urine by NMRS. Results: Based on the primary pharmacokinetic parameter, AUC(0-∞) of 5'-DFUR, equivalence was concluded for the two formulations, since the 90% confidence interval of the estimate of formulation B relative to formulation A of 97% to 107% was within the acceptance region 80% to 125%. There was no clinically significant difference between the t(max) for the two formulations (median 2.1 versus 2.0 h). The estimate for C(max) was 111% for formulation B compared to formulation A and the 90% confidence interval of 95% to 136% was within the reference region 70% to 143%. Overall, these results suggest no relevant difference between the two formulations regarding the extent to which 5'-DFUR reached the systemic circulation and the rate at which 5'-DFUR appeared in the systemic circulation. The overall urinary excretions were 86.0% and 86.5% of the dose, respectively, and the proportion recovered as each metabolite was similar for the two formulations. The majority of the dose was excreted as FBAL (61.5% and 60.3%), all other chemical species making a minor contribution. Univariate and multivariate regression analysis to explore the influence of age, gender, body surface area and creatinine clearance on the log-transformed pharmacokinetic parameters AUC(0-∞) and C(max) of capecitabine and its metabolites revealed no clinically significant effects. The only statistically significant results were obtained for AUC(0-∞) and C(max) of intact drug and for C(max) of FBAL, which were higher in females than in males. Conclusion: The bioavailability of 5'-DFUR in the systemic circulation was practically identical after administration of the two tablet formulations. Therefore, the two formulations can be regarded as bioequivalent. The variables investigated (age, gender, body surface area, and creatinine clearance) had no clinically significant effect on the pharmacokinetics of capecitabine or its metabolites.

Phase III trial of gemcitabine and carboplatin versus mitomycin, ifosfamide, and cisplatin or mitomycin, vinblastine, and cisplatin in patients with advanced nonsmall cell lung carcinoma

BACKGROUND. The authors compared gemcitabine and carboplatin (GC) with mitomycin, ifosfamide, and cisplatin (MIC) or mitomycin, vinblastine, and cisplatin (MVP) in patients with advanced nonsmall cell lung carcinoma (NSCLC). The primary objective was survival. Secondary objectives were time to disease progression, response rates, evaluation of toxicity, disease-related symptoms, World Health Organization performance status (PS), and quality of life (QoL). METHODS. Three hundred seventy-two chemotherapy-naïve patients with International Staging System Stage III/IV NSCLC who were ineligible for curative radiotherapy or surgery were randomized to receive either 4 cycles of gemcitabine (1000 mg/m2 on Days 1, 8, and 15) plus carboplatin (area under the serum concentration-time curve, 5; given on Day 1) every 4 weeks (the GC arm) or MIC/MVP every 3 weeks (the MIC/MVP arm). RESULTS. There was no significant difference in median survival (248 days in the MIC/MVP arm vs. 236 days in the GC arm) or time to progression (225 days in the MIC/MVP arm vs. 218 days in the GC arm) between the 2 treatment arms. The 2-year survival rate was 11.8% in the MIC/MVP arm and 6.9% in the GC arm. The 1-year survival rate was 32.5% in the MIC/MVP arm and 33.2% in the GC arm. In the MIC/MVP arm, 33% of patients responded (4 complete responses [CRs] and 57 partial responses [PRs]) whereas in the GC arm, 30% of patients responded (3 CRs and 54 PRs). Nonhematologic toxicity was comparable for patients with Grade 3-4 symptoms, except there was more alopecia among patients in the MIC/MVP arm. GC appeared to produce more hematologic toxicity and necessitated more transfusions. There was no difference in performance status, disease-related symptoms, of QoL between patients in the two treatment arms. Fewer inpatient stays for complications were required with GC. CONCLUSIONS. The results of the current study failed to demonstrate any difference in efficacy between the newer regimen of GC and the older regimens of MIC and MVP. © 2003 American Cancer Society.

Platinum-based chemotherapy in metastatic breast cancer : current status

Cisplatin and carboplatin are active in previously untreated patients with metastatic breast cancer (MBC) with mean response rates (RRs) of 50 and 32%, respectively. In pretreated patients the RR to cisplatin/carboplatin monotherapy declines markedly to <10%. Cisplatin and carboplatin have been combined with many other cytotoxics. In first-line setting high activity has been observed in combination with taxanes or vinorelbine (RRs consistently ∼60%). It appears that these newer combinations are superior to older regimens with etoposide (RRs 30 to 50%) or 5-fluorouracil (RRs 40 to 60%). Cisplatin-/carboplatin-based regimens with infusional 5-FU and epirubicin/paclitaxel/vinorelbine achieve high RRs of around 60 to 80%. However these regimens are difficult to administer in all patients because they require central venous access for continuous 5-FU infusion. In pretreated MBC the combinations of cisplatin-taxane/vinorelbine/gemcitabine or carboplatin-docetaxel/vinorelbine yield RRs of 40 to 50%, which are higher than those achieved with platinum-etoposide/5-FU. In locally advanced disease cisplatin-based regimens achieve very high RRs (>80%). This would suggest that in chemotherapy-naïve patients platinum-based therapy might have an important role to play. Additionally the synergy demonstrated between platinum compounds, taxanes and herceptin, in preclinical and clinical studies is of immense importance and the results of the two ongoing Breast Cancer International Research Group randomized phase III studies are eagerly awaited. These studies may help clarify the role of platinum compounds in the treatment of metastatic and possibly early breast cancer. © 2003 Elsevier Ltd. All rights reserved.

Analysis of acute-phase proteins, AHSG, C3, CLI, HP and SAA, reveals distinctive expression patterns associated with breast, colorectal and lung cancer

Early detection, clinical management and disease recurrence monitoring are critical areas in cancer treatment in which specific biomarker panels are likely to be very important in each of these key areas. We have previously demonstrated that levels of alpha-2-heremans-schmid-glycoprotein (AHSG), complement component C3 (C3), clusterin (CLI), haptoglobin (HP) and serum amyloid A (SAA) are significantly altered in serum from patients with squamous cell carcinoma of the lung. Here, we report the abundance levels for these proteins in serum samples from patients with advanced breast cancer, colorectal cancer (CRC) and lung cancer compared to healthy controls (age and gender matched) using commercially available enzyme-linked immunosorbent assay kits. Logistic regression (LR) models were fitted to the resulting data, and the classification ability of the proteins was evaluated using receiver-operating characteristic curve and leave-one-out cross-validation (LOOCV). The most accurate individual candidate biomarkers were C3 for breast cancer [area under the curve (AUC) = 0.89, LOOCV = 73%], CLI for CRC (AUC = 0.98, LOOCV = 90%), HP for small cell lung carcinoma (AUC = 0.97, LOOCV = 88%), C3 for lung adenocarcinoma (AUC = 0.94, LOOCV = 89%) and HP for squamous cell carcinoma of the lung (AUC = 0.94, LOOCV = 87%). The best dual combination of biomarkers using LR analysis were found to be AHSG + C3 (AUC = 0.91, LOOCV = 83%) for breast cancer, CLI + HP (AUC = 0.98, LOOCV = 92%) for CRC, C3 + SAA (AUC = 0.97, LOOCV = 91%) for small cell lung carcinoma and HP + SAA for both adenocarcinoma (AUC = 0.98, LOOCV = 96%) and squamous cell carcinoma of the lung (AUC = 0.98, LOOCV = 84%). The high AUC values reported here indicated that these candidate biomarkers have the potential to discriminate accurately between control and cancer groups both individually and in combination with other proteins. Copyright © 2011 UICC.

Plaintext awareness in identity-based key encapsulation

The notion of plaintext awareness ( PA ) has many applications in public key cryptography: it offers unique, stand-alone security guarantees for public key encryption schemes, has been used as a sufficient condition for proving indistinguishability against adaptive chosen-ciphertext attacks ( IND-CCA ), and can be used to construct privacy-preserving protocols such as deniable authentication. Unlike many other security notions, plaintext awareness is very fragile when it comes to differences between the random oracle and standard models; for example, many implications involving PA in the random oracle model are not valid in the standard model and vice versa. Similarly, strategies for proving PA of schemes in one model cannot be adapted to the other model. Existing research addresses PA in detail only in the public key setting. This paper gives the first formal exploration of plaintext awareness in the identity-based setting and, as initial work, proceeds in the random oracle model. The focus is laid mainly on identity-based key encapsulation mechanisms (IB-KEMs), for which the paper presents the first definitions of plaintext awareness, highlights the role of PA in proof strategies of IND-CCA security, and explores relationships between PA and other security properties. On the practical side, our work offers the first, highly efficient, general approach for building IB-KEMs that are simultaneously plaintext-aware and IND-CCA -secure. Our construction is inspired by the Fujisaki-Okamoto (FO) transform, but demands weaker and more natural properties of its building blocks. This result comes from a new look at the notion of γ -uniformity that was inherent in the original FO transform. We show that for IB-KEMs (and PK-KEMs), this assumption can be replaced with a weaker computational notion, which is in fact implied by one-wayness. Finally, we give the first concrete IB-KEM scheme that is PA and IND-CCA -secure by applying our construction to a popular IB-KEM and optimizing it for better performance.

Phase III trial comparing paclitaxel poliglumex (CT-2103, PPX) in combination with carboplatin versus standard paclitaxel and carboplatin in the treatment of PS 2 patients with chemotherapy-naïve advanced non-small cell lung cancer

INTRODUCTION: Performance status (PS) 2 patients with non-small cell lung cancer (NSCLC) experience more toxicity, lower response rates, and shorter survival times than healthier patients treated with standard chemotherapy. Paclitaxel poliglumex (PPX), a macromolecule drug conjugate of paclitaxel and polyglutamic acid, reduces systemic exposure to peak concentrations of free paclitaxel and may lead to increased concentrations in tumors due to enhanced vascular permeability. METHODS: Chemotherapy-naive PS 2 patients with advanced NSCLC were randomized to receive carboplatin (area under the curve = 6) and either PPX (210 mg/m/10 min without routine steroid premedication) or paclitaxel (225 mg/m/3 h with standard premedication) every 3 weeks. The primary end point was overall survival. RESULTS: A total of 400 patients were enrolled. Alopecia, arthralgias/myalgias, and cardiac events were significantly less frequent with PPX/carboplatin, whereas grade ≥3 neutropenia and grade 3 neuropathy showed a trend of worsening. There was no significant difference in the incidence of hypersensitivity reactions despite the absence of routine premedication in the PPX arm. Overall survival was similar between treatment arms (hazard ratio, 0.97; log rank p = 0.769). Median and 1-year survival rates were 7.9 months and 31%, for PPX versus 8 months and 31% for paclitaxel. Disease control rates were 64% and 69% for PPX and paclitaxel, respectively. Time to progression was similar: 3.9 months for PPX/carboplatin versus 4.6 months for paclitaxel/carboplatin (p = 0.210). CONCLUSION: PPX/carboplatin failed to provide superior survival compared with paclitaxel/carboplatin in the first-line treatment of PS 2 patients with NSCLC, but the results with respect to progression-free survival and overall survival were comparable and the PPX regimen was more convenient. © 2008International Association for the Study of Lung Cancer.

Single-agent versus combination chemotherapy in patients with advanced non-small cell lung cancer and a performance status of 2 : prognostic factors and treatment selection based on two large randomized clinical trials

Purpose: Data from two randomized phase III trials were analyzed to evaluate prognostic factors and treatment selection in the first-line management of advanced non-small cell lung cancer patients with performance status (PS) 2. Patients and Methods: Patients randomized to combination chemotherapy (carboplatin and paclitaxel) in one trial and single-agent therapy (gemcitabine or vinorelbine) in the second were included in these analyses. Both studies had identical eligibility criteria and were conducted simultaneously. Comparison of efficacy and safety was performed between the two cohorts. A regression analysis identified prognostic factors and subgroups of patients that may benefit from combination or single-agent therapy. Results: Two hundred one patients were treated with combination and 190 with single-agent therapy. Objective responses were 37 and 15%, respectively. Median time to progression was 4.6 months in the combination arm and 3.5 months in the single-agent arm (p < 0.001). Median survival imes were 8.0 and 6.6 months, and 1-year survival rates were 31 and 26%, respectively. Albumin <3.5 g, extrathoracic metastases, lactate dehydrogenase ≥200 IU, and 2 comorbid conditions predicted outcome. Patients with 0-2 risk factors had similar outcomes independent of treatment, whereas patients with 3-4 factors had a nonsignificant improvement in median survival with combination chemotherapy. Conclusion: Our results show that PS2 non-small cell lung cancer patients are a heterogeneous group who have significantly different outcomes. Patients treated with first-line combination chemotherapy had a higher response and longer time to progression, whereas overall survival did not appear significantly different. A prognostic model may be helpful in selecting PS 2 patients for either treatment strategy. © 2009 by the International Association for the Study of Lung Cancer.