Treatment rationale study design for the MetLung trial : a randomized, double-blind phase III study of onartuzumab (MetMAb) in combination with erlotinib versus erlotinib alone in patients who have received standard chemotherapy for stage IIIB or IV met-positive non-small-cell lung cancer

We present the treatment rationale and study design of the MetLung phase III study. This study will investigate onartuzumab (MetMAb) in combination with erlotinib compared with erlotinib alone, as second- or third-line treatment, in patients with advanced non-small-cell lung cancer (NSCLC) who are Met-positive by immunohistochemistry. Approximately 490 patients (245 per treatment arm) will receive erlotinib (150 mg oral daily) plus onartuzumab or placebo (15 mg/kg intravenous every 3 weeks) until disease progression, unacceptable toxicity, patient or physician decision to discontinue, or death. The efficacy objectives of this study are to compare overall survival (OS) (primary endpoint), progression-free survival, and response rates between the 2 treatment arms. In addition, safety, quality of life, pharmacokinetics, and translational research will be investigated across treatment arms. If the primary objective (OS) is achieved, this study will provide robust results toward an alternative treatment option for patients with Met-positive second- or third-line NSCLC. © 2012 Elsevier Inc. All Rights Reserved.

Phase II trial of Oxaliplatin and 5-Fluorouracil/Leucovorin combination in epithelial ovarian carcinoma relapsing within 2 years of platinum-based therapy

Objective To evaluate the efficacy and toxicity of Oxaliplatin and 5-Fluorouracil (5-FU)/Leucovorin (LV) combination in ovarian cancer relapsing within 2 years of prior platinum-based chemotherapy in a phase II trial. Methods Eligible patients had at least one prior platinum-based chemotherapy regimen, elevated CA-125 ≥ 60 IU/l, radiological evidence of disease progression and adequate hepatic, renal and bone marrow function. Patients with raised CA-125 levels alone as marker of disease relapse were not eligible. Oxaliplatin (85 mg/m 2) was given on day 1, and 5-Fluorouracil (370 mg/m 2) and Leucovorin (30 mg) was given on days 1 and 8 of a 14-day cycle. Results Twenty-seven patients were enrolled. The median age was 57 years (range 42-74 years). The median platinum-free interval (PFI) was 5 months (range 0-17 months) with only 30% of patients being platinum sensitive (PFI > 6 months). Six patients (22%) had two prior regimens of chemotherapy. A total of 191 cycles were administered (median 7; range 2-12). All patients were evaluable for toxicity. The following grade 3/4 toxicities were noted: anemia 4%; neutropenia 15%; thrombocytopenia 11%; neurotoxicity 8%; lethargy 4%; diarrhea 4%; hypokalemia 11%; hypomagnesemia 11%. Among 27 enrolled patients, 20 patients were evaluable for response by WHO criteria and 25 patients were evaluable by Rustin's CA-125 criteria. The overall response rate (RR) by WHO criteria was 30% (95% CI: 15- 52) [three complete responses (CRs) and three partial responses (PRs)]. The CA-125 response rate was 56% (95% CI: 37-73). Significantly, a 25% (95% CI: 9-53) radiological and a 50% (95% CI: 28-72) CA-125 response rate were noted in platinum resistant patients (PFI < 6 months). The median response duration was 4 months (range 3-12) and the median overall survival was 10 months. Conclusion Oxaliplatin and 5-Fluorouracil/ Leucovorin combination has a good safety profile and is active in platinum-pretreated advanced epithelial ovarian cancer. © 2004 Elsevier Inc. All rights reserved.

The combination of empirical mode decomposition and minimum entropy deconvolution for roller bearing diagnostics in non-stationary operation

Diagnostics is based on the characterization of mechanical system condition and allows early detection of a possible fault. Signal processing is an approach widely used in diagnostics, since it allows directly characterizing the state of the system. Several types of advanced signal processing techniques have been proposed in the last decades and added to more conventional ones. Seldom, these techniques are able to consider non-stationary operations. Diagnostics of roller bearings is not an exception of this framework. In this paper, a new vibration signal processing tool, able to perform roller bearing diagnostics in whatever working condition and noise level, is developed on the basis of two data-adaptive techniques as Empirical Mode Decomposition (EMD), Minimum Entropy Deconvolution (MED), coupled by means of the mathematics related to the Hilbert transform. The effectiveness of the new signal processing tool is proven by means of experimental data measured in a test-rig that employs high power industrial size components.

Results using Trabecular Metal™ augments in combination with acetabular impaction bone grafting in deficient acetabula

We examined whether the use of trabecular metal wedges to fill segmental defects is an effective method of socket reconstruction when used in combination with impaction grafting and implantation of a cemented socket. Fifteen hips in 14 patients underwent impaction grafting in combination with a TM wedge with a minimum of 2 years follow-up. All patients had their defects assessed using the Paprosky classification. Patients were reviewed with x-rays and migration of the implant was measured. Outcome scores were also collected. Mean follow-up was 39 months (25-83). The mean age at surgery was 67.8 (49-85) years. Seven of the patients had previously undergone impaction grafting with the use of a stainless steel rim mesh to constrain the graft. None of the patients had failed either clinically or radiologically.

Selective combination of visual and thermal imaging for resilient localization in adverse conditions : day and night, smoke and fire

Long-term autonomy in robotics requires perception systems that are resilient to unusual but realistic conditions that will eventually occur during extended missions. For example, unmanned ground vehicles (UGVs) need to be capable of operating safely in adverse and low-visibility conditions, such as at night or in the presence of smoke. The key to a resilient UGV perception system lies in the use of multiple sensor modalities, e.g., operating at different frequencies of the electromagnetic spectrum, to compensate for the limitations of a single sensor type. In this paper, visual and infrared imaging are combined in a Visual-SLAM algorithm to achieve localization. We propose to evaluate the quality of data provided by each sensor modality prior to data combination. This evaluation is used to discard low-quality data, i.e., data most likely to induce large localization errors. In this way, perceptual failures are anticipated and mitigated. An extensive experimental evaluation is conducted on data sets collected with a UGV in a range of environments and adverse conditions, including the presence of smoke (obstructing the visual camera), fire, extreme heat (saturating the infrared camera), low-light conditions (dusk), and at night with sudden variations of artificial light. A total of 240 trajectory estimates are obtained using five different variations of data sources and data combination strategies in the localization method. In particular, the proposed approach for selective data combination is compared to methods using a single sensor type or combining both modalities without preselection. We show that the proposed framework allows for camera-based localization resilient to a large range of low-visibility conditions.

Social tagging, guppy effect and the role of interference : a quantum-inspired model for tags combination

Social tagging systems are shown to evidence a well known cognitive heuristic, the guppy effect, which arises from the combination of different concepts. We present some empirical evidence of this effect, drawn from a popular social tagging Web service. The guppy effect is then described using a quantum inspired formalism that has been already successfully applied to model conjunction fallacy and probability judgement errors. Key to the formalism is the concept of interference, which is able to capture and quantify the strength of the guppy effect.

Controlled systemic release of interleukin-12 after gene electrotransfer to muscle for cancer gene therapy alone or in combination with ionizing radiation in murine sarcomas

Background: The present study aimed to evaluate the antitumor effectiveness of systemic interleukin (IL)-12 gene therapy in murine sarcoma models, and to evaluate its interaction with the irradiation of tumors and metastases. To avoid toxic side-effects of IL-12 gene therapy, the objective was to achieve the controlled release of IL-12 after intramuscular gene electrotransfer. Methods: Gene electrotransfer of the plasmid pORF-mIL12 was performed into the tibialis cranialis in A/J and C57BL/6 mice. Systemic release of the IL-12 was monitored in the serum of mice after carrying out two sets of intramuscular IL-12 gene electrotransfer of two different doses of plasmid DNA. The antitumor effectiveness of IL-12 gene electrotransfer alone or in combination with local tumor or lung irradiation with X-rays, was evaluated on subcutaneous SA-1 and LPB tumors, as well as on lung metastases. Results: A synergistic antitumor effect of intramuscular gene electrotransfer combined with local tumor irradiation was observed as a result of the systemic distribution of IL-12. The gene electrotransfer resulted in up to 28% of complete responses of tumors. In combination with local tumor irradiation, the curability was increased by up to 100%. The same effect was observed for lung metastases, where a potentiating factor of 1.3-fold was determined. The amount of circulating IL-12 was controlled by the number of repeats of gene electrotransfer and by the amount of the injected plasmid. Conclusions: The present study demonstrates the feasibility of treatment by IL-12 gene electrotransfer combined with local tumor or lung metastases irradiation on sarcoma tumors for translation into the clinical setting. Copyright © 2009 John Wiley & Sons, Ltd.

Targeted disruption of the JAK2/STAT3 pathway in combination with systemic administration of paclitaxel inhibits the priming of ovarian cancer stem cells leading to a reduced tumor burden

Chemotherapy resistance associated with recurrent disease is the major cause of poor survival of ovarian cancer patients. We have recently demonstrated activation of the JAK2/STAT3 pathway and the enhancement of a cancer stem cell (CSC)-like phenotype in ovarian cancer cells treated in vitro with chemotherapeutic agents. To elucidate further these mechanisms in vivo,we used a two-tiered paclitaxel treatment approach in nude mice inoculated with ovarian cancer cells. In the first approach, we demonstrate that a single intraperitoneal administration of paclitaxel in mice 7 days after subcutaneous transplantation of the HEY ovarian cancer cell line resulted in a significant increase in the expression of CA125, Oct4, and CD117 in mice xenografts compared to control mice xenografts which did not receive paclitaxel. In the second approach, mice were administered once weekly with paclitaxel and/or a daily dose of the JAK2-specific inhibitor, CYT387, over 4weeks. Mice receiving paclitaxel only demonstrated a significant decrease in tumor volume compared to control mice. At the molecular level, mouse tumors remaining after paclitaxel administration showed a significant increase in the expression of Oct4 and CD117 coinciding with a significant activation of the JAK2/STAT3 pathway compared to control tumors. The addition of CYT387 with paclitaxel resulted in the suppression of JAK2/STAT3 activation and abrogation of Oct4 and CD117 expression in mouse xenografts. This coincided with significantly smaller tumors in mice administered CYT387 in addition to paclitaxel, compared to the control group and the group of mice receiving paclitaxel only. These data suggest that the systemic administration of paclitaxel enhances Oct4- and CD117-associated CSC-like marker expression in surviving cancer cells in vivo, which can be suppressed by the addition of the JAK2-specific inhibitor CYT387, leading to a significantly smaller tumor burden. These novel findings have the potential for the development of CSC-targeted therapy to improve the treatment outcomes of ovarian cancer patients.

Achieving superior innovation-based performance outcomes in SMEs through innovation resource–capability complementarity

Firms are increasingly identifying new avenues to enhance their market position. One such effort involves the firms' ability to continuously learn. Learning has the capacity to enable firms to develop and implement more efficient and effective innovation-focused strategies, resulting in the ability to develop and deliver more products in a timelier manner. This study tests the relationship between innovation resource–capability complementarity and innovation-based performance. This study further elaborates that while innovation resource–capability complementarity drives innovation-based performance; their relationship will be enhanced via the firms' possession of superior learning capability. The findings show a significant effect of innovation resource–capability complementarity on innovation-based performance. The results also show that firms that possess superior learning capability are willing to question their operational processes and routines and make adjustments following the feedback obtained from customers and channels; thereby enhancing their abilities to develop more new products and increase their speed in delivering products to the customers.

Network-targeted combination therapy : a new concept in cancer treatment

Toxicity is a major concern for anti-neoplastic drugs, with much of the existing pharmacopoeia being characterized by a very narrow therapeutic index. 'Network-targeted' combination therapy is a promising new concept in cancer therapy, whereby therapeutic index might be improved by targeting multiple nodes in a cell's signaling network, rather than a single node. Here, we examine the potential of this novel approach, illustrating how therapeutic benefit could be achieved with smaller doses of the necessary agents.

Theorizing the use of multiple conceptual models in combination

Conceptual modelling continues to be an important means for graphically capturing the requirements of an information system. Observations of modelling practice suggest that modellers often use multiple conceptual models in combination, because they articulate different aspects of real-world domains. Yet, the available empirical as well as theoretical research in this area has largely studied the use of single models, or single modelling grammars. We develop a Theory of Combined Ontological Coverage by extending an existing theory of ontological expressiveness of conceptual modelling grammars. Our new theory posits that multiple conceptual models are used to increase the maximum coverage of the real-world domain being modelled, whilst trying to minimize the ontological overlap between the models. We illustrate how the theory can be applied to analyse sets of conceptual models. We develop three propositions of the theory about evaluations of model combinations in terms of users’ selection, understandability and usefulness of conceptual models.

Novel polymer synthesis methodologies using combination of thermally and photochemically-induced nitroxide mediated polymerisation

The combination of thermally- and photochemically-induced polymerization using light sensitive alkoxyamines was investigated. The thermally driven polymerizations were performed via the cleavage of the alkoxyamine functionality, whereas the photochemically-induced polymerizations were carried out either by nitroxide mediated photo-polymerization (NMP2) or by a classical type II mechanism, depending on the structure of the light-sensitive alkoxyamine employed. Once the potential of the various structures as initiators of thermally- and photo-induced polymerizations was established, their use in combination for block copolymer syntheses was investigated. With each alkoxyamine investigated, block copolymers were successfully obtained and the system was applied to the post-modification of polymer coatings for application in patterning and photografting.

Pan-Plasmodium band sensitivity for Plasmodium falciparum detection in combination malaria rapid diagnostic tests and implications for clinical management

Background: Malaria rapid diagnostic tests (RDTs) are appropriate for case management, but persistent antigenaemia is a concern for HRP2-detecting RDTs in endemic areas. It has been suggested that pan-pLDH test bands on combination RDTs could be used to distinguish persistent antigenaemia from active Plasmodium falciparum infection, however this assumes all active infections produce positive results on both bands of RDTs, an assertion that has not been demonstrated. Methods: In this study, data generated during the WHO-FIND product testing programme for malaria RDTs was reviewed to investigate the reactivity of individual test bands against P. falciparum in 18 combination RDTs. Each product was tested against multiple wild-type P. falciparum only samples. Antigen levels were measured by quantitative ELISA for HRP2, pLDH and aldolase. Results: When tested against P. falciparum samples at 200 parasites/μL, 92% of RDTs were positive; 57% of these on both the P. falciparum and pan bands, while 43% were positive on the P. falciparum band only. There was a relationship between antigen concentration and band positivity; ≥4 ng/mL of HRP2 produced positive results in more than 95% of P. falciparum bands, while ≥45 ng/mL of pLDH was required for at least 90% of pan bands to be positive. Conclusions: In active P. falciparum infections it is common for combination RDTs to return a positive HRP2 band combined with a negative pan-pLDH band, and when both bands are positive, often the pan band is faint. Thus active infections could be missed if the presence of a HRP2 band in the absence of a pan band is interpreted as being caused solely by persistent antigenaemia.

The performance advantages for SMEs of product innovation and marketing resource–capability complementarity in emerging economies

This study argues that small and medium-sized enterprises (SMEs) must possess both resources and capabilities at a superior level, and those resources and capabilities must be complementary with one another to achieve superior financial performance. The resources and capabilities of interest are product innovation and marketing. Using data from manufacturing SMEs, the results suggest that product innovation resource–capability complementarity, marketing resource–capability complementarity, and their interaction are positively related to financial performance through product innovation and customer performance. The findings suggest that some SMEs may outperform others not only because they possess a specific individual resource–capability complementarity but also because they create synergy and asset interconnectedness.

Decision boundary setting and classifier combination for text classification

This thesis presents a promising boundary setting method for solving challenging issues in text classification to produce an effective text classifier. A classifier must identify boundary between classes optimally. However, after the features are selected, the boundary is still unclear with regard to mixed positive and negative documents. A classifier combination method to boost effectiveness of the classification model is also presented. The experiments carried out in the study demonstrate that the proposed classifier is promising.