The discontinuous slip-line form of upper bound plasticity analysis is considered using an equilibrium of forces approach. It is demonstrated that the underlying basis of the approach can be written ...in terms of stress functions that provide a continuum stress state interpretation of the upper bound solution. An alternative proof of the upper bound theorem, applicable to both associative and non-associative materials, using stress functions is presented. The broader nature of the equilibrium form and the strict conditions under which it is valid are discussed, including examination of the apparent omission of moment equilibrium and associativity in many equilibrium form solutions. Finally, the relationship of the stress function formulation to the output of the computational limit analysis method discontinuity layout optimisation (DLO) and the potential to use the stress function formulation to derive a form of lower bound solution from an upper bound analysis are demonstrated.
DNA sequencing has identified recurrent mutations that drive the aggressiveness of prostate cancers. Surprisingly, the influence of genomic, epigenomic, and transcriptomic dysregulation on the tumor ...proteome remains poorly understood. We profiled the genomes, epigenomes, transcriptomes, and proteomes of 76 localized, intermediate-risk prostate cancers. We discovered that the genomic subtypes of prostate cancer converge on five proteomic subtypes, with distinct clinical trajectories. ETS fusions, the most common alteration in prostate tumors, affect different genes and pathways in the proteome and transcriptome. Globally, mRNA abundance changes explain only ∼10% of protein abundance variability. As a result, prognostic biomarkers combining genomic or epigenomic features with proteomic ones significantly outperform biomarkers comprised of a single data type.
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•A comprehensive proteomic analyses of localized prostate cancers•Integration of all levels of the central dogma (DNA → RNA → protein)•ETS fusions have divergent effects on transcriptome and proteome•Combining genomics and proteomics improves biomarker performance
Sinha et al. determine the proteogenomic landscape of localized, intermediate-risk prostate cancers and show that the presence of ETS gene fusions has one of the strongest effects on the proteome. Prognostic biomarkers that integrate multi-omics significantly outperform those comprised of a single data type.
To advance understanding of the entrepreneurship process in developing economies, this article evaluates whether registered enterprises that initially avoid the cost of registration, and focus their ...resources on overcoming other liabilities of newness, lay a stronger foundation for subsequent growth. Analyzing World Bank Enterprise Survey data across 127 countries, and controlling for other firm performance determinants, registered enterprises that started up unregistered and spent longer operating unregistered are revealed to have significantly higher subsequent annual sales, employment, and productivity growth rates compared with those that registered from the outset. The theoretical and policy implications are then discussed.
Researchers and practitioners have shown a keen interest in eco-innovation and recently developed a single instrument for measuring it. However, more in-depth endeavors in this area would not be ...possible without an adequate understanding of eco-innovation implementation and, more specifically, an appropriate instrument for measuring eco-innovation from the implementation perspective. The purpose of this study is to validate such an instrument. We collected primary data from 298 senior managers who carried out successful eco-innovation projects, and then conducted a series of statistical analyses on the data. The results show that the 17-item instrument exhibits excellent psychometric properties and is proved a reliable and valid measure.
► This study is to validate instrument of eco-innovation from the implementation perspective. ► We used data collected from 298 senior managers and then conducted a series of statistical analyses. ► The results show that the 17-item instrument exhibits excellent psychometric properties.
Although novel agents targeting the androgen-androgen receptor (AR) axis have altered the treatment paradigm of metastatic castration-resistant prostate cancer (mCRPC), development of therapeutic ...resistance is inevitable. In this study, we examined whether AR gene aberrations detectable in circulating cell-free DNA (cfDNA) are associated with resistance to abiraterone acetate and enzalutamide in mCRPC patients.
Plasma was collected from 62 mCRPC patients ceasing abiraterone acetate (n = 29), enzalutamide (n = 19), or other agents (n = 14) due to disease progression. DNA was extracted and subjected to array comparative genomic hybridization (aCGH) for chromosome copy number analysis, and Roche 454 targeted next-generation sequencing of exon 8 in the AR.
On aCGH, AR amplification was significantly more common in patients progressing on enzalutamide than on abiraterone or other agents (53% vs. 17% vs. 21%, P = 0.02, χ(2)). Missense AR exon 8 mutations were detected in 11 of 62 patients (18%), including the first reported case of an F876L mutation in an enzalutamide-resistant patient and H874Y and T877A mutations in 7 abiraterone-resistant patients. In patients switched onto enzalutamide after cfDNA collection (n = 39), an AR gene aberration (copy number increase and/or an exon 8 mutation) in pretreatment cfDNA was associated with adverse outcomes, including lower rates of PSA decline ≥ 30% (P = 0.013, χ(2)) and shorter time to radiographic/clinical progression (P = 0.010, Cox proportional hazards regression).
AR gene aberrations in cfDNA are associated with resistance to enzalutamide and abiraterone in mCRPC. Our data illustrate that genomic analysis of cfDNA is a minimally invasive method for interrogating mechanisms of therapeutic resistance in mCRPC.
Firms use open innovation strategy to explore external knowledge or exploit internal knowledge to benefit their product/service innovations, and thus enhance their innovation performance. However, a ...lack of relational mechanisms makes it more difficult for collaborative partners to share their knowledge assets. Existing literature lacks a clear explanation of how knowledge and relational mechanisms simultaneously function for innovation success. In response, this study attempts to answer: (1) Can archetypes of open innovation strategies be identified by knowledge and relational mechanisms simultaneously? And, (2) Do they differ in their ability to predict innovation success under the condition of innovation process characteristics? An exploratory study of 78 open innovation firms reflects four archetypes of open innovation strategies. A subsequent cross-industry survey of 248 open innovation firms in Taiwan reveals that the four archetypes of open innovation strategies result in varying degrees of innovation success, and innovation process characteristics positively moderate such associations.
It is increasingly evident that non–protein-coding regions of the genome can give rise to transcripts that form functional layers of the cancer genome. One of most abundant classes in these regions ...is long noncoding RNAs (lncRNAs). They have gained increasing attention in prostate cancer (PCa) and paved the way for a greater understanding of these cryptic regulators in cancer.
To review current research exploring the functional biology of lncRNAs in PCa over the past three decades.
A systematic review was performed using PubMed to search for reports with terms “long noncoding RNA”, “prostate”, and “cancer” over the past 30 yr (1988–2018).
We comprehensively surveyed the literature collected and summarise experiments leading to the characterisation of lncRNAs in PCa. A historical timeline of lncRNA identification is described, where each lncRNA is categorised mechanistically and within the primary areas of carcinogenesis: tumour risk and initiation, tumour promotion, tumour suppression, and tumour treatment resistance. We describe select lncRNAs that exemplify these areas. We also review whether these lncRNAs have a clinical utility in PCa diagnosis, prognosis, and prediction, and as therapeutic targets.
The biology of lncRNA is multifaceted, demonstrating a complex array of molecular and cellular functions. These studies reveal that lncRNAs are involved in every stage of PCa. Their clinical utility for diagnosis, prognosis, and prediction of PCa is well supported, but further evaluation for their therapeutic candidacy is needed. We provide a detailed resource and view inside the lncRNA landscape for other cancer biologists, oncologists, and clinicians.
In this study, we review current knowledge of the non–protein-coding genome in prostate cancer (PCa). We conclude that many of these regions are functional and a source of accurate biomarkers in PCa. With a strong research foundation, they hold promise as future therapeutic targets, yet clinical trials are necessary to determine their intrinsic value to PCa disease management.
This review comprehensively summarises three decades of knowledge on long noncoding RNA biology and research in prostate cancer. It systematically summarises the significant contribution of these master regulators in tumorigenesis and how this translates clinically.
Background & Aims Patients with Lynch syndrome carry germline mutations in single alleles of genes encoding the mismatch repair (MMR) proteins MLH1, MSH2, MSH6, and PMS2; when the second allele ...becomes mutated, cancer can develop. Increased screening for Lynch syndrome has identified patients with tumors that have deficiency in MMR, but no germline mutations in genes encoding MMR proteins. We investigated whether tumors with deficient MMR had acquired somatic mutations in patients without germline mutations in MMR genes using next-generation sequencing. Methods We analyzed blood and tumor samples from 32 patients with colorectal or endometrial cancer who participated in Lynch syndrome screening studies in Ohio and were found to have tumors with MMR deficiency (based on microsatellite instability and/or absence of MMR proteins in immunohistochemical analysis, without hypermethylation of MLH1 ), but no germline mutations in MMR genes. Tumor DNA was sequenced for MLH1 , MSH2 , MSH6 , PMS2 , EPCAM , POLE, and POLD1 with ColoSeq and mutation frequencies were established. Results Twenty-two of 32 patients (69%) were found to have 2 somatic (tumor) mutations in MMR genes encoding proteins that were lost from tumor samples, based on immunohistochemistry. Of the 10 remaining tumors 3 had one somatic mutation in a MMR gene, with possible loss of heterozygosity that could lead to MMR deficiency, 6 were found to be false-positive results (19%), and 1 had only one mutation in a MMR gene and remained unexplained. All of the tumors found to have somatic MMR mutations were of the hypermutated phenotype (>12 mutations/megabase); 6 had mutation frequencies >200/megabase, and 5 of these had somatic mutations in POLE , which encodes a DNA polymerase. Conclusions Some patients are found to have tumors with MMR defects during screening for Lynch syndrome, yet have no identifiable germline mutations in MMR genes. We found that almost 70% of these patients acquire somatic mutations in MMR genes, leading to a hypermutated phenotype of tumor cells. Patients with colon or endometrial cancers with MMR deficiency not explained by germline mutations might undergo analysis for tumor mutations in MMR genes to guide future surveillance guidelines.
The detection and quantification of genetic heterogeneity in populations of cells is fundamentally important to diverse fields, ranging from microbial evolution to human cancer genetics. However, ...despite the cost and throughput advances associated with massively parallel sequencing, it remains challenging to reliably detect mutations that are present at a low relative abundance in a given DNA sample. Here we describe smMIP, an assay that combines single molecule tagging with multiplex targeted capture to enable practical and highly sensitive detection of low-frequency or subclonal variation. To demonstrate the potential of the method, we simultaneously resequenced 33 clinically informative cancer genes in eight cell line and 45 clinical cancer samples. Single molecule tagging facilitated extremely accurate consensus calling, with an estimated per-base error rate of 8.4 × 10(-6) in cell lines and 2.6 × 10(-5) in clinical specimens. False-positive mutations in the single molecule consensus base-calls exhibited patterns predominantly consistent with DNA damage, including 8-oxo-guanine and spontaneous deamination of cytosine. Based on mixing experiments with cell line samples, sensitivity for mutations above 1% frequency was 83% with no false positives. At clinically informative sites, we identified seven low-frequency point mutations (0.2%-4.7%), including BRAF p.V600E (melanoma, 0.2% alternate allele frequency), KRAS p.G12V (lung, 0.6%), JAK2 p.V617F (melanoma, colon, two lung, 0.3%-1.4%), and NRAS p.Q61R (colon, 4.7%). We anticipate that smMIP will be broadly adoptable as a practical and effective method for accurately detecting low-frequency mutations in both research and clinical settings.
Despite increasing attention to the influence of customer involvement and social media in developing innovation in small- and medium-sized enterprises (SMEs), few studies have specifically ...investigated how to improve the effectiveness of social media–based customer involvement. Drawing on the knowledge-based view, social network and capability theories, we address this question by arguing that Social Customer Relation Management (CRM) enhances the effect of social media–based customer involvement upon innovation. Two key capabilities further enhance the moderating effect of Social CRM: social media network and customer information processing capabilities. The results from a longitudinal dataset of 317 SMEs indicate that SME customer involvement, enabled by Social CRM, social media network and customer information processing capabilities increases innovation. These findings have important implications for researchers and managers interested in enhancing the efficacy of SME customer involvement using social media.
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