Abstract Background and Aims Agents that induce an immune response against tumors by altering T-cell regulation have increased survival times of patients with advanced-stage tumors, such as melanoma ...or lung cancer. We aimed to characterize molecular features of immune cells that infiltrate hepatocellular carcinomas (HCCs) to determine whether these types of agents might be effective against liver tumors. Methods We analyzed HCC samples from 956 patients. We separated gene expression profiles from tumor, stromal, and immune cells using a non-negative matrix factorization algorithm. We then analyzed the gene expression pattern of inflammatory cells in HCC tumors samples. We correlated expression patterns with the presence of immune cell infiltrates and immune regulatory molecules, determined by pathology and immunohistochemical analyses, in a training set of 228 HCC samples. We validated the correlation in a validation set of 728 tumor samples. Using data from 190 tumors in the Cancer Genome Atlas, we correlated immune cell gene expression profiles with numbers of chromosomal aberrations (based on single-nucleotide polymorphism array) and mutations (exome sequence data). Results We found approximately 25% of HCCs to have markers of an inflammatory response, with high expression levels of the CD274 molecule (PD-L1) and programmed cell death 1 (PD-1), markers of cytolytic activity, and fewer chromosomal aberrations. We called this group of tumors the Immune class. It contained 2 subtypes, characterized by markers of an adaptive T-cell response or exhausted immune response. The exhausted immune response subclass expressed many genes regulated by transforming growth factor beta 1 (TGFB) that mediate immunosuppression. We did not observe any differences in numbers of mutations or expression of tumor antigens between the immune-specific class and other HCCs. Conclusions In an analysis of HCC samples from 956 patients, we found almost 25% to express markers of an inflammatory response. We identified 2 subclasses, characterized by adaptive or exhausted immune responses. These findings indicate that some HCCs might be susceptible to therapeutic agents designed to block the regulatory pathways in T cells, such as PD-L1, PD-1, or TGFB inhibitors.
The authors present findings from an analysis of articles related to product design published in eight leading journals important to marketing thought. Based on this analysis, which covers the ...fourteen‐year period 1995–2008, the authors propose a conceptual model of product design and offer definitions for (a) product design and (b) the product design process. In addition, the authors provide insights into the nature of product design research during this time period, including analyses of publication trends and the relationship of product design research to related marketing topics. The essay concludes with suggestions for future research on product design.
The authors provide synthesized summaries of research on product design conducted over the 20‐year period from 1995 to 2014, as well as suggestions for future research. Building on the conceptual ...model of product design proposed by Luchs and Swan, the current project describes research findings based on a review of 252 articles drawn from eight of the academic journals most influential to marketing thought, and identified by their inclusion of the terms “product design” or “industrial design” within their s, subject terms, and/or author supplied keywords. Specifically, the authors provide integrated summaries of 25 product design subtopics organized within Luchs and Swan's original 11 product design research topic categories, which, in turn, address the following three general product design research categories: context and strategy, product design process, and product design consequences. These summaries are followed by suggested future research opportunities to address gaps in the literature. In addition to seeking inspiration for future research based on a review of extant research, the authors illustrate an approach for exploring research opportunities based on current and emerging industry trends, such as sustainability, the sharing economy, and the emergence of consumer‐oriented health and performance management products. For each identified industry trend, the authors provide illustrative design implications with consequent illustrative research opportunities. This balanced approach to identifying near‐term research opportunities based on extant research and based on industry trends, i.e., looking forward and externally, may in turn improve the potential impact of future research on both knowledge development and on industry practice.
Data from the 2003‐2010 National Health and Nutrition Examination Survey (NHANES) indicate that about 3.6 million people in the United States have antibodies to the hepatitis C virus, of whom 2.7 ...million are currently infected. NHANES, however, excludes several high‐risk populations from its sampling frame, including people who are incarcerated, homeless, or hospitalized; nursing home residents; active‐duty military personnel; and people living on Indian reservations. We undertook a systematic review of peer‐reviewed literature and sought out unpublished presentations and data to estimate the prevalence of hepatitis C in these excluded populations and in turn improve the estimate of the number of people with hepatitis C in the United States. The available data do not support a precise result, but we estimated that 1.0 million (range 0.4 million‐1.8 million) persons excluded from the NHANES sampling frame have hepatitis C virus antibody, including 500,000 incarcerated people, 220,000 homeless people, 120,000 people living on Indian reservations, and 75,000 people in hospitals. Most are men. An estimated 0.8 million (range 0.3 million‐1.5 million) are currently infected. Several additional sources of underestimation, including nonresponse bias and the underrepresentation of other groups at increased risk of hepatitis C that are not excluded from the NHANES sampling frame, were not addressed in this study. Conclusion: The number of US residents who have been infected with hepatitis C is unknown but is probably at least 4.6 million (range 3.4 million‐6.0 million), and of these, at least 3.5 million (range 2.5 million‐4.7 million) are currently infected; additional sources of potential underestimation suggest that the true prevalence could well be higher. (Hepatology 2015;62:1353–1363)
We demonstrate the continuous and reversible tuning of the optical band gap of suspended monolayer MoS2 membranes by as much as 500 meV by applying very large biaxial strains. By using chemical vapor ...deposition (CVD) to grow crystals that are highly impermeable to gas, we are able to apply a pressure difference across suspended membranes to induce biaxial strains. We observe the effect of strain on the energy and intensity of the peaks in the photoluminescence (PL) spectrum and find a linear tuning rate of the optical band gap of 99 meV/%. This method is then used to study the PL spectra of bilayer and trilayer devices under strain and to find the shift rates and Grüneisen parameters of two Raman modes in monolayer MoS2. Finally, we use this result to show that we can apply biaxial strains as large as 5.6% across micron-sized areas and report evidence for the strain tuning of higher level optical transitions.
The importance of design as a source of value creation has been studied for decades. In the late 90s, however, a specific approach in the practice of design achieved a rapid diffusion across ...organizations: Design Thinking. This is a formal method for creative problem solving characterized by user‐centeredness, ideation, and iterative prototyping. The rapid diffusion of Design Thinking in practice has not been coupled with similarly rapid and robust development of its theoretical underpinnings. Most contributions have been inward‐oriented toward a confined community of scholars; therefore, the scientific discourse on Design Thinking has unfolded in a vacuum—often independently from other innovation management theories. The consequence has been that Design Thinking is often confused (especially among those new to the field) with the entire practice of design. Subsequently, we still lack an understanding on whether, why, and when Design Thinking contributes to innovation. In this editorial, we discuss the journey to the Special Issue “Design Thinking and Innovation Management: Matches, Mismatches and Future Avenues” that intends to critically reflect and enrich the scientific debate around Design Thinking. First, we aim at clarifying the distinction between “design” and “Design Thinking.” The former is a practice, to be studied; the latter is a paradigm, that is, a set of specific principles, methods, and tools to practice design. Second, we offer a brief overview of the community that has been investigating Design Thinking, a synthesis of the ten papers included in the Special Issue (distributed across this and the next issue), and show how they contribute to close the theoretical and empirical gaps with innovation studies. Finally, we suggest that the paradigm of Design Thinking is significantly contingent: its diffusion and success have been favored by the emergence of specific contextual conditions (substantially by the ubiquitous diffusion of digital technologies in direct interaction with users). As the context is dramatically shifting again, we wonder whether Design Thinking will keep its relevance and ability to support organizations in addressing the new challenges ahead? We address this question with the support of a contingent framework to position several design paradigms and suggest that the context ahead, where problems have multiple stakeholders and are undefined, will require the emergence of new paradigms characterized by a systemic (rather than user‐centered) and reflective (rather than ideative) practice. We therefore propose a few research questions that will hopefully encourage and shape future scholarly efforts into the study of the design practice for innovation in organizations.
ObjectiveWe previously reported a characterisation of the hepatocellular carcinoma (HCC) immune contexture and described an immune-specific class. We now aim to further delineate the immunogenomic ...classification of HCC to incorporate features that explain responses/resistance to immunotherapy.DesignWe performed RNA and whole-exome sequencing, T-cell receptor (TCR)-sequencing, multiplex immunofluorescence and immunohistochemistry in a novel cohort of 240 HCC patients and validated our results in other cohorts comprising 660 patients.ResultsOur integrative analysis led to define: (1) the inflamed class of HCC (37%), which includes the previously reported immune subclass (22%) and a new immune-like subclass (15%) with high interferon signalling, cytolytic activity, expression of immune-effector cytokines and a more diverse T-cell repertoire. A 20-gene signature was able to capture ~90% of these tumours and is associated with response to immunotherapy. Proteins identified in liquid biopsies recapitulated the inflamed class with an area under the ROC curve (AUC) of 0.91; (2) The intermediate class, enriched in TP53 mutations (49% vs 29%, p=0.035), and chromosomal losses involving immune-related genes and; (3) the excluded class, enriched in CTNNB1 mutations (93% vs 27%, p<0.001) and PTK2 overexpression due to gene amplification and promoter hypomethylation. CTNNB1 mutations outside the excluded class led to weak activation of the Wnt-βcatenin pathway or occurred in HCCs dominated by high interferon signalling and type I antigen presenting genes.ConclusionWe have characterised the immunogenomic contexture of HCC and defined inflamed and non-inflamed tumours. Two distinct CTNNB1 patterns associated with a differential role in immune evasion are described. These features may help predict immune response in HCC.
Develop a more systematic, human-centered, results-oriented thought process Design Thinking is the Product Development and Management Association's (PDMA) guide to better problem solving and ...decision-making in product development and beyond. The second in the New Product Development Essentials series, this book shows you how to bridge the gap between the strategic importance of design and the tactical approach of design thinking. You'll learn how to approach new product development from a fresh perspective, with a focus on systematic, targeted thinking that results in a repeatable, human-centered problem-solving process. Integrating high-level discussion with practical, actionable strategy, this book helps you re-tool your thought processes in a way that translates well beyond product development, giving you a new way to approach business strategy and more. Design is a process of systematic creativity that yields the most appropriate solution to a properly identified problem. Design thinking disrupts stalemates and brings logic to the forefront of the conversation. This book shows you how to adopt these techniques and train your brain to see the answer to any question, at any level, in any stage of the development process. * Become a better problem-solver in every aspect of business * Connect strategy with practice in the context of product development * Systematically map out your new product, service, or business * Experiment with new thought processes and decision making strategies You can't rely on old ways of thinking to produce the newest, most cutting- edge solutions. Product development is the bedrock of business —whether your "product" is a tangible object, a service, or the business itself — and your approach must be consistently and reliably productive. Design Thinking helps you internalize this essential process so you can bring value to innovation and merge strategy with reality.
The topic of e-cigarettes is controversial. Opponents focus on e-cigarettes' risks for young people, while supporters emphasize the potential for e-cigarettes to assist smokers in quitting smoking. ...Most US health organizations, media coverage, and policymakers have focused primarily on risks to youths. Because of their messaging, much of the public-including most smokers-now consider e-cigarette use as dangerous as or more dangerous than smoking. By contrast, the National Academies of Science, Engineering, and Medicine concluded that e-cigarette use is likely far less hazardous than smoking. Policies intended to reduce adolescent vaping may also reduce adult smokers' use of e-cigarettes in quit attempts. Because evidence indicates that e-cigarette use can increase the odds of quitting smoking, many scientists, including this essay's authors, encourage the health community, media, and policymakers to more carefully weigh vaping's potential to reduce adult smoking-attributable mortality. We review the health risks of e-cigarette use, the likelihood that vaping increases smoking cessation, concerns about youth vaping, and the need to balance valid concerns about risks to youths with the potential benefits of increasing adult smoking cessation.
Brain inflammation is a double-edged sword. It is required for brain repair in acute damage, whereas chronic inflammation and autoimmune disorders are neuropathogenic. Certain proinflammatory ...cytokines and chemokines are closely related to cognitive dysfunction and neurodegeneration. Representative anti-inflammatory cytokines, such as interleukin (IL)-10, can suppress neuroinflammation and have significant therapeutic potentials in ameliorating neurodegenerative disorders such as Alzheimer's disease (AD). Here, we show that adeno-associated virus (AAV) serotype 2/1 hybrid-mediated neuronal expression of the mouse IL-10 gene ameliorates cognitive dysfunction in amyloid precursor protein+ presenilin-1 bigenic mice. AAV2/1 infection of hippocampal neurons resulted in sustained expression of IL-10 without its leakage into the blood, reduced astro/microgliosis, enhanced plasma amyloid-β peptide (Aβ) levels and enhanced neurogenesis. Moreover, increased levels of IL-10 improved spatial learning, as determined by the radial arm water maze. Finally, IL-10-stimulated microglia enhanced proliferation but not differentiation of primary neural stem cells in the co-culture system, whereas IL-10 itself had no effect. Our data suggest that IL-10 gene delivery has a therapeutic potential for a non-Aβ-targeted treatment of AD.
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