| 1. |
- Chandran, Vineesh Indira, et al.
(författare)
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Hypoxia Attenuates Trastuzumab Uptake and Trastuzumab-Emtansine (T-DM1) Cytotoxicity through Redistribution of Phosphorylated Caveolin-1
- 2020
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Ingår i: Molecular Cancer Research. - 1541-7786 .- 1557-3125. ; 18:4, s. 644-656
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Tidskriftsartikel (refereegranskat)abstract
- The antibody-drug conjugate trastuzumab-emtansine (T-DM1) offers an additional treatment option for patients with HER2-amplified tumors. However, primary and acquired resistance is a limiting factor in a significant subset of patients. Hypoxia, a hallmark of cancer, regulates the trafficking of several receptor proteins with potential implications for tumor targeting. Here, we have investigated how hypoxic conditions may regulate T-DM1 treatment efficacy in breast cancer. The therapeutic effect of T-DM1 and its metabolites was evaluated in conjunction with biochemical, flow cytometry, and high-resolution imaging studies to elucidate the functional and mechanistic aspects of hypoxic regulation. HER2 and caveolin-1 expression was investigated in a well-annotated breast cancer cohort. Wefind that hypoxia fosters relative resistance to T-DM1 in HER2(+) cells (SKBR3 and BT474). This effect was not a result of deregulated HER2 expression or resistance to emtansine and its metabolites. Instead, we show that hypoxia-induced translocation of caveolin-1 from cytoplasmic vesicles to the plasma membrane contributes to deficient trastuzumab internalization and T-DM1 chemosensitivity. Caveolin-1 depletion mimicked the hypoxic situation, indicating that vesicular caveolin-1 is indispensable for trastuzumab uptake and T-DM1 cytotoxicity. In vitro studies suggested that HER2 and caveolin-1 are not coregulated, which was supported by IHC analysis in patient tumors. We find that phosphorylation-deficient caveolin-1 inhibits trastuzumab internalization and T-DM1 cytotoxicity, suggesting a specific role for caveolin-1 phosphorylation in HER2 trafficking.
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| 2. |
- Joshi, Sanjay. L., et al.
(författare)
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An Industrial Survey on the Influence of Process and Product Attributes on Software Product Reliability
- 2017
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Ingår i: International Conference on Networks & Advances in Computational Technologies NetACT2017. - Thiruvananthapuram, India : IEEE. - 9781509065905 ; , s. 44-51
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Konferensbidrag (refereegranskat)abstract
- Software reliability is a major attribute for software product and can be considered as one of the major performance parameters. Software Reliability unlike hardware reliability cannot be considered merely as function of time, although researchers have come up with models relating the two. In literature, numerous models on software reliability have been proposed but they seem to have limitations in being used to predict reliability in software industry. As on today, we do not have good quantitative methods developed to represent Software Reliability without excessive limitations. Various approaches can be used to improve the reliability of software, however, it is hard to balance the development time and the budget with required levels of software reliability. This paper quantitatively and qualitatively analyzes the data from an industrial survey, with focus on current practices and their dependency on the estimation of reliability in software product development environment. Analysis focuses on perception of predicting software reliability in different categories of respondents. Categorization of respondent is based on phase of development, their profile (as user, developer etc.), and application domain. While confirming some commonly known facts, our findings also show discrepancies between our perception and actual facts in some cases. The objective of this is exercise is to find out input parameters making impact on reliability. Though it is field perception, we have identified them from practitioners and taken as reference for conducting future experiments and literature survey. We believe that continued research efforts are essential to provide guidelines for reliability estimation process to take care of important but hitherto ignored factors, thus improving relevance and accuracy of reliability predictions.
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| 3. |
- Joshi, Sanjay. L., et al.
(författare)
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Do Software Reliability Prediction Models Meet Industrial Perceptions?
- 2017
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Ingår i: Proceedings of the 10th Innovations in Software Engineering Conference ISEC-2017. - New York, NY, USA : ACM. - 9781450348560 ; , s. 66-73
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Konferensbidrag (refereegranskat)abstract
- Reliability is one of the key characteristics inherent in the concept "software quality". Understanding software reliability has been vital for both the software managers and software engineers, especially while developing critical systems. In the past several decades, an extensive body of knowledge has been developed and to a certain extent practical knowledge has been gathered by applying them to large scale mission- or safety-critical projects. However, software reliability models are falling short of gaining confidence in industrial community. From the software developer's perspective, software reliability has been primarily associated with defects, which represent a major cost factor in software development. This is called developer oriented approach. As software orientation has become ubiquitous, and software intensive systems have been proliferating, software quality assurance has been embracing more customer oriented perspectives. In this context, we will need richer, realistic and more accurate measures for software reliability. A recent empirical study by the authors highlighted many factors, which the practitioners perceived to be influential in the context of reliability prediction. This paper focuses on different reliability prediction models proposed in the literature, specifically examining whether the influential factors perceived to be contributing to the reliability are addressed or not in these models. We evaluated the assumptions made in each of the considered reliability models and checked their applicability in software product development. This paper concludes with a comparative presentation of a large set of well-known reliability models with respect to the set of factors identified by the industry as influential in software reliability.
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| 4. |
- Joshi, Sanjay. L., et al.
(författare)
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Experimental analysis of dependency factors of Software Product Reliability using SonarQube
- 2019
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Ingår i: IWSM Mensura IWSM-MENSURA2019. - Harlem, Netherlands.
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Konferensbidrag (refereegranskat)abstract
- Reliability is one of the key attributes of software product quality. Capability for accurate prediction of reliability will allow software product industry to have better market acceptability and enable wider usage in high integrity or critical applications domains for their product. Software Reliability analysis is performed at various stages during software product development life cycle. Popular software reliability prediction models proposed in literature are targeted to specific phases of life cycle with certain identified parameters. However, these models seem to have certain limitations in predicting software reliability in an accurate and acceptable manner to the industry. A recent industrial survey performed by the authors identified several factors which practitioners perceived to have influence in predicting reliability. Subsequently we have conducted an elaborate set of experiments in a systematic way to validate the perceived influence of identified parameters. Reliability of software products from diverse domains and technologies were evaluated using SonarQube. In this paper, we present our experimental evaluation approach, experimental set up and results from the study. Through these controlled experiments and analysis of data, we have identified and further short-listed the probable influential factors affecting software reliability. This paper further sets direction to our future research on modeling software product reliability as a function of the identified influential factors.
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| 5. |
- Loth, Daan W, et al.
(författare)
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Genome-wide association analysis identifies six new loci associated with forced vital capacity
- 2014
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 46, s. 669-677
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Tidskriftsartikel (refereegranskat)abstract
- Forced vital capacity (FVC), a spirometric measure of pulmonary function, reflects lung volume and is used to diagnose and monitor lung diseases. We performed genome-wide association study meta-analysis of FVC in 52,253 individuals from 26 studies and followed up the top associations in 32,917 additional individuals of European ancestry. We found six new regions associated at genome-wide significance (P < 5 × 10(-8)) with FVC in or near EFEMP1, BMP6, MIR129-2-HSD17B12, PRDM11, WWOX and KCNJ2. Two loci previously associated with spirometric measures (GSTCD and PTCH1) were related to FVC. Newly implicated regions were followed up in samples from African-American, Korean, Chinese and Hispanic individuals. We detected transcripts for all six newly implicated genes in human lung tissue. The new loci may inform mechanisms involved in lung development and the pathogenesis of restrictive lung disease.
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